1786 Ann Rheum Dis: first published as 10.1136/ard.2005.036715 on 11 November 2005. Downloaded from LETTERS Joint restriction in an unhappy teenager P J C Davis, J Hackett, K Johnson, J E McDonagh ......

Ann Rheum Dis 2005;64:1786–1787. doi: 10.1136/ard.2004.034934

14 year old girl presented with a year’s history of joint (17.5 mg orally weekly) while maintaining her prednisolone pain, restriction, and swelling, initially diagnosed as at 3 mg daily. Over the following 6 months finger movement Ajuvenile idiopathic arthritis. She had no past medical improved despite stopping prednisolone in the interim. problems but had given up her leisure pursuits owing to However, she attempted suicide by taking an overdose of disability. Examination disclosed non-pitting oedema to mid- methotrexate as she felt a burden to others, and required calf; a woody texture of the soft tissues of the forearms and further psychological treatment. calves with fixed flexion deformities of her fingers, wrists, Three years after diagnosis, she remains well and continues knees, and ankles due to the soft tissue changes, and normal to receive methotrexate, with minimal inflammation on MRI, overlying skin. Investigations showed the following results: mild finger and wrist contractures, and return of full normal muscle enzymes, eosinophilia of 1.76109/l, erythro- function. At no time has there been evidence of internal cyte sedimentation rate 41 mm/1st h, haemoglobin 112 g/l, organ involvement. negative autoantibodies, and normal complement levels. The EF is characterised by painful swelling and stiffness of the differential diagnosis included eosinophilic fasciitis (EF) and extremities, typically with thickened skin (peau d’orange), a scleroderma. At this time, the patient requested counselling peripheral eosinophilia, and characteristic histology.1–4 In as she had difficulty accepting an initial misdiagnosis, contrast with adult EF, paediatric EF predominantly affects delayed correct diagnosis, and the uncertainty of the girls and has not been reported to cause haematological prognosis. complications. In contrast with scleroderma, the epidermis Magnetic resonance imaging (MRI) of the forearm was and dermis are spared, whereas in comparison with performed (fig 1). A biopsy showed chronic inflammatory polymyositis there is minimal muscle inflammation, distinc- 1–4 changes in the deep subcutaneous fat and fascia with tions illustrated by MRI. infiltration by lymphocytes, plasma cells, histiocytes, and Teenage self harm is well recognised, particularly in girls, although may be underdiagnosed in those with a chronic eosinophils. The fascia was markedly thickened and fibrosed 5 with focal fibrinoid necrosis, consistent with EF. illness. The impact of the disease itself, its impact upon body In view of her disability, she was treated with intravenous image and lifestyle, and the side effects of treatment, lack of predictability, and uncertainty of prognosis are all likely to methylprednisolone (1 g/day for 3 days), then oral predniso- contribute to mental health status during adolescence.6 lone 20 mg daily (0.3 mg/kg/day) with normalisation of her Prognosis in paediatric EF remains uncertain, although a erythrocyte sedimentation rate and eosinophilia. Methotrexate previous study has reported more favourable outcomes in 15 mg orally weekly was added 2 months later as there had 4 older children. We expect to withdraw methotrexate from http://ard.bmj.com/ been no further significant clinical response to steroids. this girl within the next 12–18 months if her signs and MRI Five months later she improved functionally with reduced appearance remains stable. This case highlights the use of contractures despite prednisolone reduction to 12.5 mg daily. MRI in assessment of soft tissue disease and in guiding drug A repeat MRI scan showed a reduction in the subcutaneous management. Furthermore, the psychological impact during and fascial oedema, prompting a further reduction in adolescence of a chronic disease, its management, and correct steroids. At this time, she self harmed by cutting the skin diagnosis should not be underestimated. of her forearms because of low mood, difficulties adjusting to her diagnosis, and the cosmetic side effects of steroids. She JEMcD is an Arthritis Research Campaign clinical senior lecturer. on September 26, 2021 by guest. Protected copyright. required treatment with antidepressants and counselling. One year after diagnosis, an MRI scan showed persistent ...... fascial oedema, leading to an increase in methotrexate Authors’ affiliations P J C Davis, J Hackett, Department of Rheumatology, Birmingham Children’s Hospital, UK K Johnson, Department of Radiology, Birmingham Children’s Hospital, UK J E McDonagh, Institute of Child Health, University of Birmingham, Birmingham, UK

Correspondence to: Dr J E McDonagh, Institute of Child Health, Birmingham Children’s Hospital and University of Birmingham, Steelhouse Lane, Birmingham B4 6NH, UK; [email protected]

Accepted 23 April 2005

REFERENCES 1 De Clerck LS, Degryse HR, Wouters E, Van Offel JF, De Schepper AM, Martin JJ, et al. Magnetic resonance imaging in the evaluation of patients with eosinophilic fasciitis. J Rheumatol 1989;16:1270–3. 2 Liou CH, Huang GS, Taylor JAM, Juan CJ, Gao HW, Chen CY. Eosinophilic Figure 1 Coronal short t inversion recovery (STIR) image of arm. The fasciitis in a military recruit: MRI evaluation with clinical correlation. Skeletal white arrows indicate areas of high signal oedema within the fascia. Radiol 2003;32:52–7.

www.annrheumdis.com Letters 1787 Ann Rheum Dis: first published as 10.1136/ard.2005.036715 on 11 November 2005. Downloaded from

3 Cassidy JT, Petty RE. Textbook of pediatric rheumatology, 4th ed. 5 Hawton K, Rodham K, Evans E, Weatherall R. Deliberate self-harm in Philadelphia: Saunders, 2001. adolescents: self report survey in schools in England. BMJ 4 Farrington ML, Haas JE, Nazar-Stewart V, Mellins E. Eosinophilic fasciitis in 2002;325:1207–11. children frequently progresses to scleroderma-like cutaneous fibrosis. 6 Suris JC, Michaud PA, Viner R. The adolescent with a chronic condition. Part I: J Rheumatol 1993;20:128–32. Developmental isssues. Arch Dis Child 2004;8:938–42.

Relapse of autoimmune diseases after autologous T cell depleted stem cell transplantation may be triggered by T cells recently emigrated from the thymus IKo¨tter*, T Daikeler*, H Einsele, S Koch, L Lochmann, L Kanz, J Lo¨ffler ......

Ann Rheum Dis 2005;64:1787–1789. doi: 10.1136/ard.2004.032870

igh dose immunosuppressive therapy with subsequent (TRECs) were measured by real time polymerase chain autologous stem cell transplantation (ASCT) has reaction using the light cycler (Roche Diagnostics proved effective for treatment resistant autoimmune Corporation, Idaho, USA). The study was approved by the H 1 diseases. However, in a number of patients, relapses of local ethics committee and patients’ informed consent autoimmune disease after initial improvement or even obtained. remission occur. Until recently, it was impossible to All patients improved considerably (all patients with SSc) differentiate recent thymic emigrants from residual or or went into remission (PsA, WG) after ASCT. In all patients, peripherally expanded T cells. Douek and coworkers2 and previous immunosuppressive therapy was discontinued, later our group3 described a method for detection of T cell except in the patient with WG, who still received ciclosporin receptor excision circles, stable DNA episomes which are A for her kidney transplant. Two patients relapsed after 7, formed during T cell receptor rearrangement in the thymus and 19 months, respectively (one SSc, one PsA). CD3+/CD4+ which are not replicated during mitosis, but are diluted T cells were recovered after 6–14 months (median 12), and during cell divisions.4 This study aimed at investigating CD3+/CD8+ T cells a maximum of 3 months after ASCT in all whether these flares are associated with de novo T cell patients. Autoantibodies disappeared in four of five patients development. after a median of 6 months and their recurrence or Peripheral blood mononuclear cells were collected from six disappearance later did not correlate with relapse or patients, mean age 32.5 years, range 24–42 (four with remission. TRECs could not be detected in the patients systemic sclerosis (SSc), one with Wegener’s granulomatosis shortly after ASCT (week 2), but recurred 9–26 months (WG), one with mutilating psoriatic arthritis (PsA)), after (median 16 months) after ASCT. In the two patients who high dose immunosuppression with cyclophosphamide experienced relapses, TRECs became detectable at the time http://ard.bmj.com/ 50 mg/kg body weight plus anti-thymocyte globulin 20 mg/ when the first symptoms of relapse were noticed (SSc, kg on days 1–4, with subsequent retransfusion of 4.26106 patient No 3: relapse after 7 months, TRECs after 9 months; (median) CD34+ selected (by CliniMacs device) cells/kg body PsA, patient no 4: relapse after 19, TRECs after 21 months— weight. Blood collection was performed at week 2 and then, the blood collection did not always coincide exactly with the at bimonthly intervals, genomic DNA was extracted using the diagnosis of relapse, which explains the 2 months’ difference QIAmp DNA Blood Mini Kit. DNA was stored at 280˚C until between diagnosis and first detection of TRECs) (fig 1,

analysis. T cell receptor rearrangement excision circles table 1). on September 26, 2021 by guest. Protected copyright.

TREC detection Figure 1 First detection of TRECs and relation to diagnosis of relapse. Patient 1, WG

Patient 2, SSc

Patient 3, SSc Relapse

Patient 4, PsA Relapse

Patient 5, SSc

Patient 6, SSc

03 96 12 15 18 21 24 27 30 33 36 39 Time (months)

www.annrheumdis.com 1788 Letters Ann Rheum Dis: first published as 10.1136/ard.2005.036715 on 11 November 2005. Downloaded from e h e e W H I ™exge IGPVH exe IGITH IGSIPH xu™leoli TQ xe xh V RS xh PI QH xe xe ISFS xe QRFP IRFT xe nspe™ifi™ FS hx hx hx HI IR ™exge IGIQH IGTH xh xu™leoli SW xh xh QQ IQQ xh PU xh xh PI IRFI PVFQ IQFU IQ PPFR RHFQPSFP xeg hx WP IGSHH xeg xu™leoli IGSIPH ™exge TT IT xh xh IR QH IU IQ IS xh xh xh IHFU PUFW IWFU IV QHFI RUFU TQSH UQVH xe xh QQQT TWI hx F RI F IGIHHH xu™leoli IGSIPH xh exe UR ITFT PR xh PP PSFU xh QI xh xh IP QIQTx ISFW xh PRFI PQFI PVFP SPFU xh FR UP F PI V x xeg IGSIPH xu™leoli xh UU PI IP PP PW IW QH PW T V HhSxhQQ RHxhQS VFT ITFR PQFI PPFV PSFU SQ UVWH xh xh hI h R Q S R x HI ™exge IGVH xh xh SP P SU U U F PQPQQ Ux F IGVH xh xh IGSIPH IS IH S SPFP SUFT C hRx PR UI ƒglEUH xh xu™leoli xh IH xh W http://ard.bmj.com/ hUUTTVSx hR hI xu™leoli IGTH xh xh ™exge IGSIPH T C Sx F H Rx exeD ƒglEUH ™exge IGSHH xh xu™leoli xh xh U C on September 26, 2021 by guest. Protected copyright. QP QR xu™leoli IGSSHD ƒglEUH ™exge IGSHH xu™leoli IGIVH T QW HVRQPP PS ™exge IGIHHH exe IGITH xu™leoli IGSIPH xh IS IQPQPI PP PQIU S xh IH IQ IS IU IV PS IR IU IT xh IT IT IU II IR xh xh IT PH PH RR RS RP PQ xh QR xh xh RI RI QS QQ QH PQ II IS IW xh PP PP xh RFR IP IP IS IU IIFV IQFR PRFR PH QHFT xh PSFR PWFI PSFW S UV UW VP VQVQVH UW IS ISFU PQFU xh PP PSFH xh QIFV PWFR QH xh IU IWFW IWFR RRFU PSFV RUFQU xh nspe™ifi™ xh nspe™ifi™ xeg nspe™ifi™ xeg RRSRRSR R I RRSQx PI ITUUx UT F ™exge IGSHH exe IG IHHH xu™leoli IGISPH TH VH TQIV II TFP xh S e H g U E l x IH SUUUWVI VI g e IGSIP RH H IGSSH II QPWFT IVFV PHFV IU xh WFW IRFS PHPS IFT RSFW IT IUFS PI UFT QP H PH I QT RFS IR H QV H T U T HFQI IGSIPH xone xh UUUH UHIH WRUH WRVH WIHH xh STUH WSHH UUPH UPHH UTPH SVIH SUVH RTQH TPQH RPWH PPIH QTUH QTWH QRWH RWIH RUUH RSRH RUQH QWHH RHTH RPWH xe SHIH SPRH RRVH TIVH TIRH xh UUIH UUIH xh IHSIH IHQIH UIQH TWHH TWVH TVWH UIQH TRSH SVUH WWRH SUIH VRVH UPVH TPQH VRHH QWIH UHSH STHH RWSH SQPH RWPH UVWH TISH UIHH UTSH VTSH VWSH TPVH IIPQH UVSH TURH VVVH TVVH IISRH xh VVTH IIRUH UHQH SRQH UPWH IHPIH IHRRH l smmune re™onstitutionD —uto—nti˜ody titresD —nd „‚igs of the p—tients ˜efore —nd —t regul—r interv—ls —fter stem ™ell tr—nspl—nt—tion m R @€seA T @ƒƒ™A vympho™ytes @7A I S @ƒƒ™A €—tient xoveuko™ytesG I @‡qA ‡eekP H @ƒƒ™A Q@ƒƒ™A ‡eek P ‡eek IT ‡eek PR ‡eek QT ‡eek RV ‡eek TH ‡eek UP ‡eek WH ‡eek IHT ‡eek IPP ‡eek IQV ‡eek IUP ‡eek PHR P QPWR PRFR S T ghR @7A IP PUQWIVITIUxhIVxhPRPVPSPVxh QS R R V xhxhIUIWPQPQxhPWxhQ S RWIS T ghPH @7A I PQWH S H xhPPPPIWIUPHISPHIWFVxhIUIP RSTI W H QTPUQHRSRVFTxhRVRVxhRIxhxhxhxe UUTTxhxhSPRRRQ S UI QSP Q VVPhWWUSQR QT xhxe TghV @7A I TQTP IVIVPPxhPWPWQUQS ghST @7A IP TP QPH H QR VW S TeutoEe˜ QT I™ Pƒ Qxu™leoli R „—˜le I

www.annrheumdis.com Letters 1789 Ann Rheum Dis: first published as 10.1136/ard.2005.036715 on 11 November 2005. Downloaded from

Normally, immune reconstitution and TREC recurrence is considerably quicker in ASCT than in allogeneic SCT.5 TREC recurrence in the allogeneic setting is known to be delayed by 6 5 clinical events such as graft versus host disease, whereas in 10 ASCT CD34+ selection of the graft was associated with 6 NA ND NA ND ND 8 increased thymic output (‘‘rebound phenomenon’’).2 In the present study, T cell ontogenesis was delayed even in comparison with allogeneic SCT for haematological diseases 5 (TREC recurrence: 6 months6). Premature immunosenes- 10 6 1 Neg NA ND ND ND ND ND cence may be one of the reasons for this delay in T cell ontogenesis after ASCT in autoimmune diseases.78 De novo T cell ontogenesis in the thymus may be a critical

4 event inducing relapses of the autoimmune disease, which

10 may not be caused by peripheral expansion of memory T cells 6 ND 1 ANA 1/1000 ND ND ND ND which survived the conditioning treatment, but by newly developed T cells of thymic origin. Vice versa, as in four patients TRECs recurred without relapse of the autoimmune disease, one might also argue that the occurrence of TRECs is not causally associated with relapse. Further studies of the ND ND 1/500 ND ND ND ND immune reconstitution, correlating the recurrence of TRECs with T cell subsets, T cell receptor diversity, and autoantibody production in patients with autoimmune diseases after ASCT 4

10 will improve our understanding of the pathogenesis of these 6 ND Neg ANA ND ND ND diseases and help in the development of new therapeutic concepts.

...... 4

10 Authors’ affiliations 6 ANA 1/500 ND Neg ND Neg Neg NA ND IKo¨tter, T Daikeler, H Einsele, S Koch, L Lochmann, L Kanz, J Lo¨ffler, Tu¨bingen University, Hospital, Department of Internal Medicine II,

+ Otfried-Mu¨ller-Str 10, D-72076 Tu¨bingen, Germany 4

10 *The first and second authors contributed equally to this work. 6 1/500 ANA 1/1000, Nucleoli 1/180, SCl-70 ND ND Correspondence to: Dr I Ko¨tter, [email protected] + 4 Accepted 15 May 2005 10 6 1/160, SCl-70 REFERENCES 1 Tyndall A, Matucci-Cerinic M. Haematopoietic stem cell transplantation for the treatment of systemic sclerosis and other autoimmune disorders. Expert Opin Biol Ther 2003;3:1041–9. http://ard.bmj.com/ ND ANA NDND ND ND ND ND ND None ND 2 Douek DC, Vescio RA, Betts MR, Brenchley JM, Hill BJ, Zhang L, et al. Assessment of thymic output in adults after haematopoietic stem-cell 5

+ transplantation and prediction of T-cell reconstitution. Lancet 4 10 2000;355:1875–81. 6 10

6 3 Loeffler J, Bauer R, Hebart H, Douek DC, Rauser G, Bader P, et al. Unspecific Neg Neg ANA ANA 1/300, Nucleoli 1/180, SCl-70 Quantification of T-cell receptor excision circle DNA using fluorescence resonance energy transfer and the LightCycler system. J Immunol Methods

+ 2002;271:167–75.

4 Hazenberg MD, Verschuren MC, Hamann D, Miedema F, van Dongen JJ. T on September 26, 2021 by guest. Protected copyright. cell receptor excision circles as markers for recent thymic emigrants: basic ANA 1/1000 ANA 1/1500, SCl-70 aspects, technical approach, and guidelines for interpretation. J Mol Med 2001;79:631–40.

+ 5 Peggs KS, Mackinnon S. Immune reconstitution following haematopoietic stem cell transplantation. Br J Haematol 2004;124:407–20. 6 Hazenberg MD, Otto SA, de Pauw ES, Roelofs H, Fibbe WE, Hamann D, et al. ANA 1/500, Nucleoli 1/120 None None ND None None None 4 1/500 SCl-70 None None None None 6 None None 1.4 None None None None None 6 ND None None None NDT-cell receptor None excision None circleand 6 T-cell dynamics after allogeneic stem cell transplantation are related to clinical events. Blood 2002;99:3449–53. 7 Weyand CM, Fulbright JW, Goronzy JJ. Immunosenescence, autoimmunity, and rheumatoid arthritis. Exp Gerontol 2003;38:833–41. 8 Koetz K, Bryl E, Spickschen K, O’Fallon WM, Goronzy JJ, Weyand CM. T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci USA ANA 1/500 SCl-70 ANA 2000;97:9203–8. quantified) ND ND quantified) ND ND ND ND ND ND ND ND Continued Patient No5 Week 0 Week 2 SCl-70 (not Week 16 Week 24 Week 364 Week 48 Week 60 Week 72 Week 90 Week 106 Week 122 Week 138 Week 172 Week 204 6 SCl-70 (not TREC 1 ND ND None None 2 6 3 ND, not done; NA, not available, neg: negative. Week 0, week before conditioning; week 2, 2 weeks after peripheral blood stem cell transplantation (retransfusion of autologous stem cells). 5 2 Table 1

www.annrheumdis.com 1790 Letters Ann Rheum Dis: first published as 10.1136/ard.2005.036715 on 11 November 2005. Downloaded from Altered influenza virus haemagglutinin peptides inhibit T cell responses to type II collagen in rheumatoid arthritis L Xia, L Ru, L Zhanguo ......

Ann Rheum Dis 2005;64:1790–1791. doi: 10.1136/ard.2005.039305

heumatoid arthritis (RA) is a T cell mediated auto- immune disease and associated with HLA-DR4 or HLA- Table 1 IFNc and IL4 production by PBMC of RA RDR1 subtypes.12 Type II collagen (CII) has been stimulated by altered HA308–317 peptides implicated as an autoantigen of RA, and CD4+ T cell Stimulators IFNc (pg/ml) IL4 (pg/ml) responses to CII or CII derived peptides are mainly presented (10 mg/ml) (n = 10) (n = 10) by HLA-DR4/1 molecules.34 Inhibition of antigen presenta- tion by HLA-DR4/1 molecules can interfere with T cell Medium 32.1 (15.8)* 25.9 (3.5) mediated autoimmune responses in RA. CII263–272 77.3 (60.8) 28.1 (4.9) APL1 37.8 (14.1)* 26.5 (5.1) Our previous studies have suggested that altered CII263– APL2 37.1 (23.5)* 29.6 (4.0) 272 peptides inhibited CII263–272-induced T cell activation APL3 34.8 (19.0)* 28.9 (6.9) by blocking antigen presentation.56In this study we examine the role of the altered influenza virus haemagglutinin (HA) Results are shown as mean (SD). To find whether the altered HA308–317 peptides affected cytokine 308–317 peptides (altered peptide ligands (APLs)) with single profile, supernatants of PBMC were evaluated for IFNc or IL4 production or multiple substitutions of T cell receptor (TCR) contact from 10 patients with RA with the altered HA308–317 peptides or residues in T cell responses of peripheral blood mononuclear CII263–272 stimulation. The levels of IFNc in the supernatants from cells (PBMC) and inhibitory effects of APLs on CII263–272- PBMC stimulated with CII263–272 were significantly higher than those incubated with medium alone(*p,0.05). In contrast, aPL down regulated induced T cell activation in RA. IFNc production in the supernatants from PBMC, compared with CII263– Twenty seven HLA-DR4/1 positive patients with RA (21 272 (*p,0.05). No differences of IL4 productions in the supernatants female, 6 male; mean (SD) age 53.6 (13.3) years; mean (SD) were found when T cells in PBMC from patients with RA were stimulated disease duration 10.4 (8.4) years) were included in the study. with CII263–272 or APLs. All patients fulfilled the American College of Rheumatology revised criteria for the classification of RA. Of 27 patients with RA, 24 (89%) were positive for DR4 and 3 (11%) for used to detect the levels of interferon c (IFNc) or interleukin DR1. (IL) 4 in the supernatants. Sequences of three APLs and CII263–272 were T cell proliferative responses to APLs in PBMC from RA YVAQNTLKLA (APL1), YAKQATLKLA (APL2), YAKQATLALA were 7.4% for APL1, 3.7% for APL2 or APL3, which were (APL3), and FKGEQGPKGE, respectively. T cell proliferation lower than for CII263–272 (62.2%). The mean (SD) SI values experiments were performed by [3H]thymidine incorporation for T cell responses to APLs were 1.2 (0.4) for APL1, 1.3 (0.4) http://ard.bmj.com/ assay. PBMC (2.06105/well) were incubated with CII263–272 for APL2, and 1.1 (0.4) for APL3, which were significantly or APLs at 10 mg/ml for 5 days. In competitive studies, PBMC lower than for CII263–272 (2.0 (0.8)). In addition, it was were preincubated with various concentrations of APLs as shown that T cell proliferative responses to CII263–272 were indicated for 2 hours before addition of CII263–272. Cultures suppressed by APLs in a dose dependent manner in a range were pulsed with [3H]thymidine (0.25 mCi/well) before the from 2.0 mg/ml to 50 mg/ml (fig 1). last 12 hours. The data are presented as the stimulation index The levels of IFNc were significantly increased when (SI). Enzyme linked immunosorbent assay (ELISA) kits were stimulated with CII263–272 (77.3 (60.8) pg/ml), compared

with the levels of 37.8 (14.1) pg/ml for APL1, 37.1 (23.5) pg/ on September 26, 2021 by guest. Protected copyright. ml for APL2, and 34.8 (19.0) pg/ml for APL3, which were 3.0 0 similar to the level for unstimulated control (32.1 (15.8) pg/ ml). No significant differences were found in IL4 production 2.5 2 10 when PBMC were stimulated with APLs or CII263–272 2.0 50 (table 1). In this study we assessed T cell responses to APLs in

SI 1.5 patients with RA and demonstrated that T cell responses to CII263–272 could be inhibited by the APLs with substitutions 1.0 of the TCR contact residues. HA306–318 peptide can bind to HLA-DR4/1 molecules with a much higher affinity than 0.5 CII263–272.7 Altered HA306–318 peptides with the substitu- 0.0 tions of TCR contact residues are not recognised by HA- APL1 APL2 APL3 specific T cell clones, although these peptide analogues still Altered HA308–317 peptides (µg/ml) bind to DR4/1.8 Therefore, altered HA peptides might be more efficient antagonist peptides in the inhibition of immune Figure 1 Inhibitory effects of altered HA308–317 peptides on T cell responses induced by HLA-DR4/1-specific peptides. responses to CII263–272. PBMC from patients with RA were cultured for The mechanism by which APLs antagonise T cell responses 5 days in the presence of 10 mg/ml CII263–272 and different m cannot be based on HLA-DR blockade only. Alternatively, concentrations of altered HA308–317 peptides (0, 2, 10, and 50 g/ 910 ml, respectively). Results showed that altered HA308–317 peptides APLs may alter the cytokine production profile of T cells. suppressed T cell responses to CII263–272 in a range from 2 mg/ml to In this study we showed that APLs down regulated the 50 mg/ml (*p,0.05,**p,0.01). production of IFNc compared with CII263–272, which

www.annrheumdis.com Letters 1791 Ann Rheum Dis: first published as 10.1136/ard.2005.036715 on 11 November 2005. Downloaded from promoted IFNc secretion. These results suggest that APLs are 2 Gonzalez-Gay MA, Garcia-Porrua C, Hajeer AH. Influence of human leukocyte antigen-DRB1 on the susceptibility and severity of rheumatoid not Th1 stimulators. It is not clear whether they regulate Th2 arthritis. Semin Arthritis Rheum 2002;31:355–60. cells because no effects on IL4 production were found in the 3 Sekine T, Kato T, Masuko-Hongo K, Nakamura H, Yoshino S, Nishioka K, et present study. Further studies are necessary to investigate al. Type II collagen is a target antigen of clonally expanded T cell in the synovium of patients with rheumatoid arthritis. Ann Rheum Dis whether APLs effectively inhibit T cell activation in vivo, such 1999;58:446–50. as in the HLA-DR4 transgenic animal model. 4 Diab BY, Lambert NC, L’Faqihi FE, Loubet-Lescoulie P, de Preval C, Coppin H. Human collagen II peptide 256–271 preferentially binds to HLA-DR molecules associated with susceptibility to rheumatoid arthritis. Immunogenetics 1999;49:36–44. This work was supported by National Science Foundation of China 5 Qiang Z, Yongjing C, Houshan L, Weihong Z, Zhanguo L. Inhibition of T cell (30271223) and National Outstanding Youth Grant of China activation with HLA-DR1/DR4 restricted non-T-cell stimulation peptides. Hum (30025040). Immunol 2003;64:857–65. 6 Yongjing C, Qiang Z, Zhanguo L. The inhibitory effect of altered collagen II peptide on HLA-DRB1-restricted T-cell activation. Scand J Immunol ...... 2005;61:260–5. Authors’ affiliations 7 Rosloniec EF, Whittington KB, Zaller DM, Kang AH. HLA-DR1 (DRB1*0101) L Xia, L Ru, L Zhanguo, Department of Rheumatology and Immunology, and DR4 (DRB1*0401) use the same anchor residues for binding an People’s Hospital, Peking University, 11 Xizhimen South St, Beijing immunodominant peptide derived from human type II collagen. J Immunol 2002;168:253–9. 100044, China 8 Rothbard JB, Busch R, Howland K, Bal V, Fenton C, Taylor WR, et al. Structural analysis of a peptide—HLA class II complex: identification of critical Correspondence to: Dr L Zhanguo, [email protected] interactions for its formation and recognition by T cell receptor. Int Immunol 1989;1:479–86. Accepted 13 April 2005 9 Singh RA, Zhang JZ. Differential activation of ERK, p38, and JNK required for Th1 and Th2 deviation in myelin-reactive T cells induced by altered peptide ligand. J Immunol 2004;173:7299–307. REFERENCES 10 Singh RA, Zang YC, Shrivastava A, Hong J, Wang GT, Li S, et al. Th1 and Th2 deviation of myelin-autoreactive T cells by altered peptide ligands is 1 Weyand CM, Goronzy JJ. T cell response in rheumatoid arthritis: systemic associated with reciprocal regulation of Lck, Fyn, and ZAP-70. J Immunol abnormalities-local disease. Curr Opin Rheumatol 1999;11:210–17. 1999;163:6393–402.

Relationship between 5,10-methylenetetrahydrofolate reductase C677T gene polymorphism and methotrexate related toxicity in patients with autoimmune diseases receiving folic acid supplementation M Speletas, N Papadopoulos, C Daiou, E Katodritou, A Pavlitou-Tsiontsi, V Galanopoulou ......

Ann Rheum Dis 2005;64:1791–1792. doi: 10.1136/ard.2005.037218 http://ard.bmj.com/

he common polymorphism C677T of the 5,10-methylene- tetrahydrofolate reductase (MTHFR) gene reduces Table 1 Patients’ characteristics enzyme activity and it has recently been associated with T Adverse effects on September 26, 2021 by guest. Protected copyright. increased incidence of methotrexate (MTX) related toxicity in patients with cancer and rheumatoid arthritis.1–5 Considering Present Absent that folate supplementation may reduce toxicity without Characteristics (n = 15) (n = 48) affecting MTX efficiency, we conducted a retrospective study Age (years) to analyse the effect of this polymorphism in patients with Mean (SD) 56.8 (10.8) 52.6 (16.6) Range 33–72 20–81 autoimmune diseases receiving folate supplementation. Sex (F/M) 11/4 (2.75) 33/15 (2.2) Sixty three patients (F/M: 44/19, mean age 53.6 years, Disease range 20–81) with autoimmune diseases who had been Rheumatoid arthritis 13 33 treated with MTX (7.5–15 mg/week, mean duration Psoriatic arthritis 2 10 Ankylosing spondylitis – 3 35.8 months, range 2–121), were selected from the out- Polymyositis – 2 patient clinic between January and June 2004. Five of them Disease duration (months) had discontinued MTX treatment at the time of selection, Mean (SD) 36.6 (30.1) 35.6 (29.6) because of adverse events or inefficiency. Thirty nine of the Range 2–121 5–120 Additional drugs (No (%) of patients) patients were receiving a combination of MTX with cortico- Corticosteroids (only) 2 (13) 7 (15) steroids and/or other disease modifying antirheumatic drugs. Other DMARDs (¡ corticosteroids) 8 (53) 22 (46) All the patients were prescribed supplementary 2.5 mg folic MTHFR genotype, No (%) acid the day before and the day after MTX treatment. All CC (wild type) 10 (67) 13 (27) CT (heterozygous) 3 (20) 28 (58) participants were informed and consented to take part in the TT (homozygous) 2 (13) 7 (15) study. Table 1 shows the characteristics of the patients. Genomic DNA was extracted from peripheral blood, and DMARDs, disease modifying antirheumatic drugs (included ciclosporin: 9 analysis of the MTHFR C677T polymorphism was performed patients, hydroxychloroquine: 7 patients, and infliximab: 14 patients).

www.annrheumdis.com 1792 Letters Ann Rheum Dis: first published as 10.1136/ard.2005.036715 on 11 November 2005. Downloaded from studies did not receive folate supplementation, or they received it after the emergence of toxicity. Interestingly, other studies did not support such a correlation.78A possible explanation of our results, similar to the protective effect of the MTHFR C677T polymorphism in carcinogenesis,910is that this polymorphism, in the presence of adequate folate supply, results in sustained ability of DNA synthesis and repair through increased synthesis of purines and thymidine, and subsequently in decreased MTX related toxicity. In conclusion, our data suggest that a folate supply is critical among patients with autoimmune diseases and different MTHFR genotypes. When folic acid is given, subjects with MTHFR 677TT and C677T may be at reduced Figure 1 MTHFR C677T gene polymorphism established by PCR- 6 risk of MTX related toxicity, probably because of the digestion by HinfI. The protocol of Frosst and coworkers was followed, sustained ability of DNA synthesis. This protective effect is with some modifications. The forward and reverse primers used were 59-TGAAGGAGAAGGTGTCTGCGGGA-39 and absent in subjects with MTHFR 677CC and in subjects with 59-AGGACGGTGCGGTGAGAGTG-39, respectively. The PCR MTHFR 677TT and C677T receiving MTX without folate conditions were 2 minutes at 94˚C followed by 32 cycles (94˚C for supply, as has been shown in previous studies. In addition, 30 seconds, 62˚C for 30 seconds, 72˚C for 60 seconds), and 5 minutes our results indicate the importance of genotyping to provide at 72˚C after the last cycle. A 198 bp fragment was amplified by PCR useful information for individualised treatment in patients and subjected to HinfI digestion (New England Biolabs, UK). The 677T allele contains an HinfI site resulting in 175 bp and 23 bp fragments, with autoimmune diseases. whereas a C at position 677 (677C) does not. The PCR and digestion products were analysed in 3% TBE agarose gels. Samples were ...... categorised as homozygous for the thermolabile variant (677TT, lane 2), Authors’ affiliations heterozygous for wild type and variant (C677T, lanes 1 and 3), or wild M Speletas, C Daiou, E Katodritou, A Pavlitou-Tsiontsi, Haematology type (677CC, lane 4). Bl, negative control; M, 100 bp ladder molecular and Immunology Department, Papageorgiou General Hospital, weight marker (Invitrogen, UK). The 23 bp fragments were not visible on Thessaloniki, Greece agarose gels. N Papadopoulos, V Galanopoulou, Rheumatology Unit, Papageorgiou General Hospital, Thessaloniki, Greece by polymerase chain reaction (PCR) amplification followed Correspondence to: Dr M Speletas, Dimarchou K Tsirou 8, 54248 by restriction digestion analysis (fig 1). The statistical Thessaloniki, Greece; [email protected] analysis was performed with SPSS statistical software. The prevalence of the MTHFR C677T genotype in our Accepted 14 April 2005 cohort of patients was 37% for 677CC (23/63 patients), 49% for C677T (31/63 patients), and 14% for 677TT (9/63 patients). Fifteen (24%) patients displayed one or more REFERENCES adverse effects (three nausea, eight neutropenia/pancytope- 1 Borchers AT, Keen CL, Cheema GS, Gershwin ME. The use of methotrexate in nia, two a rise in transaminases, and three oral mucositis) rheumatoid arthritis. Semin Arthritis Rheum 2004;34:465–83. 2 Ulrich CM, Yasui Y, Storb R, Schubert MM, Wagner JL, Bigler J, et al. and six of them discontinued MTX because of toxicity. Pharmacogenetics of methotrexate: toxicity among marrow transplantation Moreover, a further four patients discontinued MTX, one patients varies with the methylenetetrahydrofolate reductase C677T because of inefficiency, one because of emergence of polymorphism. Blood 2001;98:231–4. http://ard.bmj.com/ 3 van Ede AE, Laan RFJM, Blom HJ, Huizinga TWJ, Haagsma GJ, secondary amyloidosis, and two because of emergence of Giesendorf BAJ, et al. The C677T mutation in the methylenetetrahydrofolate neoplasia (total discontinuation 16%). There was no sig- reductase gene. A genetic risk for methotrexate-related elevation of liver nificant difference in the MTX dosage, the demographic and enzymes in rheumatoid arthritis patients. Arthritis Rheum 2001;44:2525–30. clinical features between the patients with and without 4 Urano W, Taniguchi A, Yamanaka H, Tanaka E, Nakajima H, Matsuda Y, et al. Polymorphisms in the methylenetetrahydrofolate reductase gene were adverse effects during MTX treatment. associated with both the efficacy and the toxicity of methotrexate used for the Interestingly, toxicity was more common in patients with treatment of rheumatoid arthritis, as evidenced by single locus and haplotype normal genotype than in those with both heterozygotes and analysis. Pharmacogenetics 2002;12:183–90. 5 Toffoli G, Russo A, Innocenti F, Corona G, Tumolo S, Sartor F, et al. Effect of on September 26, 2021 by guest. Protected copyright. homozygotes (p = 0.005 analysed by Fisher’s exact test). methylenetetrahydrofolate reductase 677CRT polymorphism on toxicity and Moreover, in multivariate analysis of variance the MTHFR homocysteine plasma level after chronic methotrexate treatment with ovarian genotype was the most important independent risk factor cancer patients. Int J Cancer 2003;103:244–9. predisposing to MTX related toxicity (p = 0.042), compared 6 Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in with the other variables analysed—namely, age, sex, dura- methylenetetrahydrofolate reductase. Nature Genet 1995;10:111–17. tion, and type of treatment (MTX alone or in combination 7 Kumagai K, Hiyama K, Oyama T, Maeda H, Kohno N. Polymorphisms in the with corticosteroids and/or other disease modifying anti- thymidine synthase and methylenetetrahydrofolate reductase genes and rheumatic drugs). sensitivity to the low-dose methotrexate therapy in patients with rheumatoid arthritis. Intern J Mol Med 2003;11:593–600. To our knowledge, this is the first study illustrating an 8 Berkun Y, Levartovsky D, Rubinow A, Orbach H, Aamar S, Grenader T, et al. inverse relationship between an MTHFR C677T variant and Methotrexate related adverse effects in patients with rheumatoid arthritis are MTX related toxicity, in which the presence of toxicity was associated with the A1298C polymorphism of the MTHFR gene. Ann Rheum Dis 2004;63:1227–31. more common in patients with the normal 677CC genotype. In 9 Chen J, Giovannucci E, Kelsey K, Rimm EB, Stampfer MJ, Colditz GA, et al. A previous studies the presence of an MTHFR C677T polymorph- methylenetetrahydrofolate reductase polymorphism and the risk of colorectal ism was associated with a higher incidence of MTX related cancer. Cancer Res 1996;56:4862–4. toxicity in patients with rheumatoid arthritis and cancer, and 10 Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, et al. Polymorphisms in the methylenetetrahydrofolate reductase gene are also with an increased risk of discontinuing MTX treatment associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci because of adverse events.2–5 However, most patients in those USA 1999;96:12810–15.

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Primary antiphospholipid syndrome: a unique presentation with multiple visceral aneurysms V Koutoulidis, A Chatziioannou, C Kostopoulos, S Kontogiannis, V Skiadas, D Mourikis, L Vlahos ......

Ann Rheum Dis 2005;64:1793–1794. doi: 10.1136/ard.2004.034975

e present a unique case of a young woman with a pathogenesis of such aneurysms in primary APS—such as proven primary type of antiphospholipid syndrome in our case—remains unclear.6 W(APS) and multiple abdominal visceral aneurysms. Kong et al reported a case of a young man with systemic Only one other case with such an association has been lupus erythematosus and secondary APS who presented with reported before to our knowledge. The presence of visceral acute abdominal pain owing to a ruptured right hepatic aneurysms poses a therapeutic challenge because the anti- artery aneurysm.4 He was also found to have aneurysms of coagulation treatment may be catastrophic in view of the risk the left hepatic artery and splenic artery on necropsy. The of aneurysm rupture and abdominal bleeding. aetiology of these aneurysms according to the authors and A 38 year old woman was transferred from the department based on histological examination of the aneurysmal wall, of obstetrics and gynaecology of the hospital, because of was found to be systemic lupus erythematosus vasculitis. peripheral oedema. Two days earlier she had had a third Dongola and Foord described a case of primary APS trimester pregnancy loss. She had a history of four presenting with varied arterial abnormalities.6 These included unexplained deaths of morphologically normal fetuses at the presence of a large number of micro- and macro- the third trimester, during the past 10 years. She was the aneurysms of hepatic, renal, and mesenteric arteries. There mother of a healthy 7 year old child. A diagnosis of primary was insufficient evidence to merit a concurrent diagnosis of APS was made based on clinical and serological criteria. polyarteritis nodosa or other associated systemic condition. Anticardiolipin IgG antibodies were present at a moderate The authors suggested that the arterial abnormalities in level (48 GPL units; normal ,19 GPL). There was no this patient might have been inherent to the syndrome itself evidence of a concurrent systemic disease as documented in and that APS can present protean vascular abnormalities, all detailed laboratory examinations performed for almost which represent a wide spectrum without associated 1 year. Computed tomography of the abdomen disclosed vasculitis. multiple partially thrombosed and calcified visceral aneur- Our case is a further example of the unusual presentation ysms affecting the splenic, hepatic, and both renal arteries, of APS without any association with other syndromes, as which were further documented with selective angiography shown by all laboratory examinations and documented by (fig 1). The course of the patient’s disease was uneventful for postmortem histological examination of the diseased arteries. 3 years, but progressive pulmonary, renal, and hepatic Based on a literature review, we did anticoagulate the patient malfunction then started to develop. She progressively because there was serious concern about thromboembolic deteriorated and died from multiorgan failure. Postmortem disease, despite the presence of multiple intra-abdominal 78 examination confirmed the presence of the splachnic aneurysms. We also followed all the other treatment http://ard.bmj.com/ aneurysms without any evidence of rupture. protocols, including steroids and plasmapheresis, with the APS is one of the most important causes of hypercoagul- intention of provoking regression of the aneurysms. Such a ability.1 About 50% of patients with APS do not have an regression was noted in a case of APS associated with associated systemic disease and are labelled as cases of polyarteritis nodosa, with a significant decrease in both the primary APS.23 The association of APS and arterial aneur- number and size of splachnic aneurysms after intensive ysms is controversial and poses a critical therapeutic treatment.5 In our case this treatment was unsuccessful dilemma. Lifelong anticoagulation remains the fundamental because the postmortem examination showed the presence of treatment for APS and may obviously be hazardous in the the aneurysms, albeit without any evidence of aneurysm on September 26, 2021 by guest. Protected copyright. presence of multiple aneurysms. Although in most cases rupture or internal bleeding. of secondary APS the presence of arterial aneurysms can Despite the fact that the patient received all the appropriate be attributed to the underlying systemic disease,45 the supportive treatment, her disease progressed and she

Figure 1 Contrast enhanced computed tomography of the abdomen (A) shows large, partially thrombosed aneurysms of the splenic and hepatic arteries (arrows). Multiple splenic artery aneurysms are confirmed on selective angiography (B).

www.annrheumdis.com 1794 Letters Ann Rheum Dis: first published as 10.1136/ard.2005.036715 on 11 November 2005. Downloaded from eventually died from multiorgan failure. Oral anticoagulation Correspondence to: Mr V Koutoulidis, [email protected] probably prevented the development of major arterial and venous thromboembolic disease, without causing the rupture Accepted 18 April 2005 of any of the pre-existing aneurysms. However, anticoagula- tion did not prevent the progression to multiorgan failure, REFERENCES which can be attributed to alterations in the microvascular 1 Harris EN. Syndrome of the black swan. Br J Rheumatol 1987;26:324–6. circulation. 2 Asherson RA, Khamashta MA, Ordi-Ros J, Derksen RH, Machin SJ, In conclusion, we think that multiple splachnic aneurysms Barquinero J, et al. The primary antiphospholipid syndrome: major clinical and serological features. Medicine (Baltimore) 1989;68:366–74. probably represent part of the spectrum of vascular abnorm- 3 Vianna JL, Khamashta MA, Ordi-Ros J, Font J, Cervera R, Lopez-Soto A, et al. alities of primary APS. If such aneurysms are identified, Comparison of the primary and secondary antiphospholipid syndrome: a lifetime anticoagulation should still be considered as the European multicenter study of 114 patients. Am J Med 1994;96:3–9. 4 Kong KO, Koh ET, Lee HY, Wee KP, Feng PH. Abdominal crisis in a young preferred treatment in order to prevent deep venous man with systemic lupus erythematosus. Lupus 2002;11:186–9. thrombosis and/or pulmonary embolism, despite the risk of 5 Dasgupta B, Almond MK, Tanqueray A. Polyarteritis nodosa and the bleeding complications. antiphospholipid syndrome. Br J Rheumatol 1997;36:1210–12. 6 Dongola NA, Foord KD. Angiographic features associated with antiphospholipid syndrome. Br J Radiol 2000;73:1215–18...... 7 Derksen RH, de Groot PG, Kater L, Nieuwenhuis HK. Patients with Authors’ affiliations antiphospholipid antibodies and venous thrombosis should receive long term V Koutoulidis, A Chatziioannou, C Kostopoulos, S Kontogiannis, anticoagulant treatment. Ann Rheum Dis 1993;52:689–92. 8 Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The V Skiadas, D Mourikis, L Vlahos, Areteion University Hospital, 76 Vas. management of thrombosis in the antiphospholipid-antibody syndrome. Sophias Avenue, 11527 Athens, Greece N Engl J Med 1995;332:993–7.

A family with diffuse idiopathic skeletal hyperostosis C Gorman, A S M Jawad, I Chikanza ......

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e report a family with diffuse idiopathic skeletal normal and HLA-B27 was negative. An x ray examination hyperostosis (DISH). The most striking occurrence showed normal sacroiliac joints, advanced osteophytosis and Wwas severe cervical disease without extensive dorsal degeneration of the hip joints, and ankylosis of the cervical involvement. From the tissue typing results of our two sibling spine (fig 1C). His hip disease required prompt replacement patients, it appears less likely that, if there is a hereditary surgery. component, it is linked to HLA status. It remains to be seen All these patients had radiological changes suggestive of whether this is a new disease entity or an unusual familial DISH. Two of this patient’s siblings also had the disease, as variant of DISH. We are unaware of a similar published do his other two offspring (they are receiving care at different http://ard.bmj.com/ report. hospitals). The first two patients described here were tissue A 23 year old man was referred with a painful stiff neck of typed: these siblings only shared alleles at DRB3 and the C 3 years’ duration. On examination, all movements of his locus, which occur frequently in the general population. cervical spine were restricted. Other spinal movements were DISH is an ossifying, non-inflammatory, non-erosive normal. Inflammatory markers were normal and HLA-B27 enthesopathy favouring the dorsal spine but sparing the was negative. An x ray examination of the sacroiliac joints, sacroiliac joints. By contrast, ankylosing spondylitis is an thoracic and lumbar spine were unremarkable. However, the inflammatory condition with enthesopathies facing joints, on September 26, 2021 by guest. Protected copyright. cervical spine radiograph showed gross anterior osteophytosis always affecting the sacroiliac joints. DISH affects 3–6% of (fig 1A). the population over 40 years of age and 11% aged over This man’s 24 year old sister had been seen 7 years 70 years.1 It is twice as common in men and occurs more previously. She described a 6 year history of worsening neck frequently in certain racial groups: it is common in Japanese pain and stiffness. On examination, movements of the and Pima Indians but rare in black and Asian races.1 Other cervical spine were severely limited in all directions, with causes of hyperostosis or bony excrescences include spondy- mild limitation of the thoracic spine. An x ray examination litis deformans, ankylosing spondylitis, trauma, fluorosis, and inflammatory markers were normal and HLA-B27 was treatment with retinoids, ochronosis, acromegaly, hypo- negative. Five years later, the clinical findings had scarcely parathyroidism, and x-linked hypophosphataemic osteo- changed. However, although the sacroiliac joints were still malacia, but there was nothing in the history, physical normal, there was now marked osteophytosis around the hip examination, or the investigations to suggest that our three joints with gross osteophytosis and ankylosis of the cervical patients had any of those conditions.2 spine (fig 1B). Two years later, this advanced cervical In the cervical spine, ossification of the posterior long- pathology precipitated cervical myelopathy. itudinal ligament (OPLL) is commonly seen. This phenom- The father of these patients was first seen at 52 years of age enon is often called ‘‘Japanese disease’’ owing to its despite having a ‘‘30 year history of ankylosing spondylitis’’. predominance in the Japanese population.3 OPLL displays a He had a strong family history of the disease, with brother, strong genetic component with high concordance in twins sister, and mother affected. On examination, all spinal and families.45 Various modes of inheritance have been movements were markedly reduced. Movements of both suggested, including HLA linkage.6 In DISH, however, hips were severely restricted and bilateral elbow fixed flexion although there are racial differences, no strong familial deformities were present. Inflammatory markers were tendency has been demonstrated. Neither is there a proven

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Figure 1 Lateral x ray findings of the cervical spine of the son (A), the daughter (B), and the father (C), showing severe anterior osteophytosis.

HLA link, as found between HLA-B27 and the spondyloar- Correspondence to: Dr A S M Jawad, The Royal London Hospital, thropathies. Bancroft Road, London E1 4DG, UK; [email protected] Although our patients were diagnosed as DISH, there are some atypical features. The most striking of these is severe Accepted 3 May 2005 cervical disease without extensive dorsal involvement. Forestier and Rotes-Querol in their classification criteria, REFERENCES considered involvement of at least three intervertebral bodies 1 Mazieres B, Rovensky J. Non-inflammatory enthesopathies of the spine: a 7 in the dorsal spine to be essential. However, Utsinger’s diagnostic approach. Bailliere’s Clinical Rheumatol 2000;14:201–17. criteria do not include this as a necessary feature.8 One 2 Utsinger PD. Diffuse idiopathic skeletal hyperostosis. Clin Rheum Dis similar case has been described: a 71 year old patient 1985;11:325–51. 3 Ono K, Yonenobu K, Miyamoto S, Okada K. Pathology of ossification of the presented with similar cervical findings and sparing of the posterior longitudinal ligament and ligament flavum. Clin Orthop Relat Res dorsal spine and sacroiliac joints. Difficulty was found 1999;359:18–26. classifying the condition as either DISH or ankylosing 4 Koga H, Sakou T, Taketomi E, Hayashi K, Numasawa T, Harata S, et al. 9 Genetic mapping of ossification of the posterior longitudinal ligament of the spondylitis. Another unusual feature in our cases is the spine. Am J Genet 1998;62:1460–7. strong familial pattern. From the tissue typing results of our 5 Hamanishi C, Tan A, Yamane T, Tomihara M, Fukuda K, Tanaka S. two sibling patients, it appears less likely that, if there is a Ossification of the posterior longitudinal ligament. Autosomal trait. Spine hereditary component, it is linked to HLA status. 1995;20:205–7. 6 Matsunga S, Yamaguchi M, Hayashi K, Sakou T. Genetic analysis of It thus remains to be seen whether this is a new disease ossification of the posterior longitudinal ligament. Spine 1999;21:937–8. entity or an unusual familial variant of DISH. 7 Forestier J, Rotes-Querol J. Senile ankylosing hyperostosis of the spine. Ann Rheum Dis 1950;9:321–30...... 8 Utsinger PD. Diffuse skeletal hyperostosis (DISH, ankylosing hyperostosis). In:

Moskowitz RW, Howell DS, Goldberg VM, Mankin HJ, eds. Osteoarthritis. http://ard.bmj.com/ Authors’ affiliations Diagnosis and management. Philadelphia: Saunders, 1984:225–33. C Gorman, A S M Jawad, I Chikanza, Rheumatology Department, 9 Helfenstein M. Severe cervical ankylosis – DISH, AS or what? Br J Rheumatol Newham University Hospital, Glen Road, London E13 8SL, UK 1989;28:299–303. on September 26, 2021 by guest. Protected copyright. Antiphospholipid antibodies in patients with scleroderma: prevalence and clinical significance G Sanna, M L Bertolaccini, A Mameli, G R V Hughes, M A Khamashta, A Mathieu ......

Ann Rheum Dis 2005;64:1795–1796. doi: 10.1136/ard.2005.038430

ntiphospholipid antibodies (aPL) are detected in a b2-glycoprotein I (anti-b2GPI), and antibodies to phosphati- variety of autoimmune disorders, most commonly dylserine-prothrombin complex (aPS-PT) in 25 patients with systemic lupus erythematosus, but also in some scleroderma (18 with limited and 7 with diffuse scleroderma, A 1 infectious diseases, lymphoproliferative disorders, and even as defined by LeRoy et al ) (table 1). Twenty four patients in apparently healthy people. were female (median age 50 years (range 28–70), median Although a wide prevalence of aPL in systemic sclerosis has disease duration 3 years (range 1–20)). One patient had a been reported (between 0 and 41%), most studies have history of venous thrombosis. Of the 17 patients who had focused on anticardiolipin antibodies (aCL) and very little is ever been pregnant, five had an adverse obstetric history. Two known about other aPL in this disease. We determined patients had miscarriages (before the 10th week of gesta- the prevalence and clinical significance of aCL, antibodies to tion), two patients had a fetal death (at the 10th week of

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Table 1 Clinical characteristics of patients with Table 2 Distribution of aPL in patients with scleroderma scleroderma* and controls

Limited Diffuse All Scleroderma Limited Diffuse Controls Characteristics (n = 18) (n = 7) (n = 25) (n = 25) (n = 18) (n = 7) (n = 100)

Calcinosis 2 1 3 Any aPL 8 6 2 5 Raynaud’s phenomenon 17 6 23 aCL 6 5 1 5 Oesophageal dysmotility 9 4 13 IgG 4 3 1 3 Sclerodactyly 17 5 22 IgM 2 2 0 2 Telangiectasia 6 2 8 Anti-b2GPI 2 2 0 3 Pulmonary manifestations 11 5 16 IgG 1 1 0 2 Interstitial lung disease 10 5 15 IgM 1 1 0 1 Pulmonary hypertension 3 0 3 aPS-PT 3 2 1 0 Cardiac manifestations 1 0 1 IgG 0 0 0 0 Renal manifestations 0 0 0 IgM 3 2 1 0 Bowel disease 0 0 0

*All patients were attending the 2nd Chair of Rheumatology, Rheumatology Division and Centre for Systemic Rheumatic Diseases, Cagliari University Hospital, Cagliari, Italy. telangiectasia and pulmonary hypertension, supporting the data from Hasegawa et al in their cohort of 112 patients with 9 gestation or later), and one patient had a premature birth scleroderma. Overall, these findings suggest that aPS-PT (before the 34th week of gestation) due to severe pre- may be a marker of vascular involvement in patients with eclampsia. Platelet count was normal in all patients. Only one scleroderma. However, as this is a very small study, further patient had a prolonged activated partial thromboplastin research is warranted to confirm or reject this hypothesis. time. One hundred healthy donors with no relevant medical In summary, aPL are commonly found in patients with history comprised the control group. scleroderma but the ‘‘typical’’ clinical manifestations of antiphospholipid syndrome are not frequently seen in these aCL, anti-b2GPI, and aPS-PT were detected by enzyme linked immunosorbent assay (ELISA).2–4 patients. aPL were present in 8/25 patients. Table 2 shows the ...... distribution of aPL in patients and controls. aCL for IgG/IgM Authors’ affiliations and aCL IgG were more frequently found in patients with G Sanna, M L Bertolaccini, G R V Hughes, M A Khamashta, Lupus scleroderma than in controls (24% v 5%, odds ratio = 6 (1.7– Research Unit, The Rayne Institute, King’s College London School of 21.7), p = 0.008 and 16% v 3%, odds ratio = 6.1 (1.2–2.9), Medicine, St Thomas’ Hospital, London, UK p = 0.03, respectively). The prevalence of anti-b2GPI did not G Sanna, A Mameli, A Mathieu, Cattedra di Reumatologia II, Universita` differ between patients and controls (8% v 3% for IgG/IgM, di Cagliari, Cagliari, Italy 4% v 2% for IgG, and 4% v 1% for IgM). G Sanna, Department of Rheumatology, Homerton University NHS Interestingly, patients with telangiectasia and pulmonary Foundation Trust, London, UK hypertension had IgM aPS-PT more frequently than those Correspondence to: Dr M A Khamashta, [email protected] without (37.5% v 0%, relative risk = 4.4 (2.0–9.5), p = 0.02 and 66.6% v 4.5%, relative risk = 14.6 (1.8–116.9), p = 0.03, Accepted 16 April 2005 respectively). No associations were found between the other aPL analysed and clinical manifestations of scleroderma. http://ard.bmj.com/ One patient with scleroderma who had had venous REFERENCES thrombosis also had IgG aCL at low titres. Of the two 1 LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. patients with a history of miscarriages (,10th week of J Rheumatol 1988;15:202–5. gestation), one had IgG anti-b2GPI and the other IgM aPS- 2 Harris EN, Pierangeli S, Birch D. Anticardiolipin wet workshop report. Fifth PT. None of the patients who had fetal death (n = 2) or International Symposium on antiphospholipid antibodies. Am J Clin Pathol prematurity (n = 1) had aPL. 1994;101:616–24. 3 Amengual O, Atsumi T, Khamashta MA, Koike T, Hughes GRV. Specificity of

Although the presence of all aPL was more common in ELISA for antibody to beta 2-glycoprotein I in patients with antiphospholipid on September 26, 2021 by guest. Protected copyright. patients with scleroderma than in healthy controls (32% v syndrome. Br J Rheumatol 1996;35:1239–43. 5%), the clinical manifestations of antiphospholipid syn- 4 Bertolaccini ML, Atsumi T, Koike T, Hughes GR, Khamashta MA. Antiprothrombin antibodies detected in two different assay systems. drome were not frequently seen in these patients. Prevalence and clinical significance in systemic lupus erythematosus. Thromb The prevalence of aCL in scleroderma has been reported to Haemost 2005;93:289–97. range from 0%5 to 41%.6 In this study, only one patient had a 5 Fonollosa V, Selva A, Lima J, Simeon CP, Vilardell M. Anticardiolipin antibodies in systemic sclerosis. J Am Acad Dermatol 1991;25:133–4. history of venous thrombosis and aCL at low titres, 6 Passaleva A, Massai G, Matucci-Cerinic M, Domeneghetti MP, Sharifian J, suggesting that this manifestation may have been aCL Lotti T, et al. Immunological abnormalities in a group of patients with limited related. cutaneous systemic sclerosis and prominent vascular disease. Autoimmunity 1990;6:283–91. Parodi et al described anti-b2GPI in 3/90 (3.3%) patients 7 7 Parodi A, Drosera M, Barbieri L, Rebora A. Antiphospholipid antibody system with scleroderma, whereas Schoenroth et al reported a in systemic sclerosis. Rheumatology (Oxford) 2001;40:111–12. prevalence of 8% when studying 26 patients with this 8 Schoenroth L, Fritzler M, Lonzetti L, Senecal JL. Antibodies to beta2 disease.8 These studies are in agreement with our findings. glycoprotein I and cardiolipin in SSc. Ann Rheum Dis 2002;61:183–4. 9 Hasegawa M, Sato S, Yanaba K, Komura K, Yamazaki M, Takehara K. Although the prevalence of aPS-PT was low in our study, Autoantibodies against phosphatidylserine-prothrombin complex in patients these antibodies were more frequently found in patients with with systemic sclerosis. Ann Rheum Dis 2004;63:1514–17.

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oedem— @‚ƒQ€iA is simil—r to polymy—lgi— rheum—ti™— phenotypeF €—tients ID PD —nd Rh—d oedem— in the h—nds —nd

‚ @€w‚A in th—t it shows —rthr—lgi— —ttri˜ut—˜le to feetD whi™h is typi™—l of ‚ƒQ€iD while p—tient Q h—d mus™le

tenosynovitis —nd mus™le p—inD o™™urring most ™ommonly p—in —loneD suggestive of €w‚F €—tient P w—s di—gnosed —s

in the elderlyD —nd shows — good response to ™orti™osteroid h—ving ‚ƒQ€i —sso™i—ted with €w‚ —t the onset of dise—seD

I±R

tre—tmentF „he —etiologies of ‚ƒQ€i —nd €w‚ —re still ˜ut —t rel—pse the p—tient h—d €w‚ symptoms —loneF e

unknownD ˜ut they —re sometimes —sso™i—ted with neopl—sti™D

possi˜le expl—n—tion for these findings is th—t ‚ƒQ€i —nd

ST

other rheum—ti™D or infe™tious dise—sesF €w‚ m—y ˜e ™l—ssifi—˜le —s the s—me dise—se entity with their

rereD we report ™lini™—l findings in four p—tients with symptoms of multiple tenosynovitisD —nd m—ny tr—nsition—l

IP

‚ƒQ€i or €w‚D or ˜othD —fter infe™tion with wy™opl—sm— „he ™lini™—l forms h—ve ™lini™—l fe—tures of ˜oth disordersF

pneumoni—eF sn™re—ses in infl—mm—tory re—™tions were seen in phenotypes m—nifested —fter infe™tion with w pneumoni—e

—ll p—tientsD —nd the fin—l di—gnoses were ‚ƒQ€i —lone in m—y ˜e dependent on the hostEdise—se rel—tionshipF

p—tients I —nd RD ‚ƒQ€i —sso™i—ted with €w‚ in p—tient PD

ƒever—l lines of eviden™e suggest th—t wy™opl—sm— spe™ies

UV

—nd €w‚ —lone in p—tient Q @t—˜le IAF xone of the p—tients ™—n ™—use rheum—ti™ disordersF €revious exposure to

h—d — he—d—™he or ˜lurred vision suggestive of —sso™i—ted wy™opl—sm— spe™ies is ™ommonly ™onfirmed ˜y immuno˜lotE

tempor—l —rteritisF ‚e™ent infe™tion with w pneumoni—e w—s ting in p—tients with rheum—toid —rthritis or juvenile

™onfirmed in —ll p—tients ˜y the presen™e of sgw —nti˜ody to rheum—toid —rthritisD ˜ut polymer—se ™h—in re—™tion showed

this —gent in the serum —nd the results of seri—l serologi™—l

no dete™t—˜le hxe of these —gents in the synovi—l fluid or

W studies with or without — positive ™old —gglutin—tion testF

e prospe™tive epidemiologi™—l study in henm—rk tissueF

ƒerum sgw levels were within the norm—l limits in —ll

indi™—ted th—t the in™iden™e of €w‚ v—ried in p—r—llel with

p—tientsD —nd none showed positive results for serologi™—l IH

„hese findings epidemi™s of w pneumoni—e infe™tionF

tests for other infe™tious —gents or —uto—nti˜odies su™h —s

indire™tly suggest th—t wy™opl—sm— spe™ies m—y ˜e rel—ted to

rheum—toid f—™tor or —ntinu™le—r —nti˜odyF ell p—tients were

the development of rheum—ti™ disordersD —nd the present

tre—ted su™™essfully with or—l prednisoloneD ˜ut two rel—psed

™—ses represent import—nt dire™t eviden™e of the involvement

during the t—pering of this drugF

of w pneumoni—e in the —etiology of ‚ƒQ€iG€w‚F purther

„here —re three possi˜le ™h—r—™teristi™s of ‚ƒQ€iG€w‚ —fter

studies in l—rger num˜ers of p—tients —re ne™ess—ry to ™l—rify

w pneumoni—eF „he first is the presen™e of infe™tion with http://ard.bmj.com/

the p—thogeneti™ me™h—nism of ‚ƒQ€iG€w‚ —fter infe™tion

™ommon ™oldElike symptoms pre™eding ‚ƒQ€iG€w‚F „wo of

with this —gentF the four p—tients showed ™ommon ™oldElike symptomsD —nd

—nti˜ioti™s were given to p—tient xo I ˜e™—use ™hest r—diogr—phy

FFFFFFFFFFFFFFFFFFFFF demonstr—ted ˜il—ter—l pleur—l effusion due to —™tive infe™tion

euthors9 —ffili—tions with w pneumoni—eF „he extremely high g re—™tive protein level

w w—tsud—D ‰ ƒhimojim—D „ qonoD ‡ sshiiD u u—nekoD w ‰—z—kiD with —n —lmost norm—l erythro™yte sediment—tion r—te in

ƒEi sked—D „hird hep—rtment of wedi™ineD ƒhinshu niversity ƒ™hool of p—tient I m—y h—ve refle™ted previous infe™tion with this —gentF

on September 26, 2021 by guest. Protected copyright. wedi™ineD w—tsumotoD t—p—n

„he se™ond ™h—r—™teristi™ is the frequent o™™urren™e of

rel—pseF ‚ƒQ€i usu—lly shows — good response to ™orti™osterE

gorresponden™e toX hr w w—tsud—D „hird hep—rtment of wedi™ineD

oid tre—tmentD —nd is gener—lly unlikely to rel—pse during

ƒhinshu niversity ƒ™hool of wedi™ineD QEIEI es—hiD w—tsumoto QWHE

I±R

t—pering of drug tre—tmentF roweverD rel—pse o™™urred soon VTPID t—p—nY m—tsud—dhspFmdFshinshuEuF—™Fjp

—fter the st—rt of t—pering of or—l prednisolone in two p—tients

@xos I @fig IA —nd PA in the present studyF e™™epted PQ epril PHHS

„—˜le I €—tient ™h—r—™teristi™s

v—˜or—tory tests —t onset „re—tment —t onset

€re™eding

™ommon e˜norm—l sgw —nti˜ody iƒ‚B gold

™oldElike €—tient ynset hi—gnoses findings on g‚€B @mmG hi—gnoses to w €rednisolone —gglutin—tion

symptoms xo —geGsex —t onset ™hest x r—y Ist hA @mgGlA —t rel—pse pneumoni—e @mgGd—yA enti˜ioti™s test

I VPGp ‚ƒQ€i C PR III C ± C PH C ‚ƒQ€i

P UUGp ‚ƒQ€i —nd C PQ PS C ±±PH±€w‚

€w‚

QUSGw€w‚± PSQQC ±±PH±±

R UPGp ‚ƒQ€i ± QH IQ CC ±PH±±

Bxorm—l v—luesX iƒ‚ Q±II mmGIst hY g‚€ DI mgGlF

g‚€D g re—™tive proteinY iƒ‚D erythro™yte sediment—tion r—teY €w‚D polymy—lgi— rheum—ti™—Y ‚ƒQ€iD remitting seroneg—tive symmetri™—l synovitis with pitting oedem—F

www.annrheumdis.com 1798 Letters Ann Rheum Dis: first published as 10.1136/ard.2005.036715 on 11 November 2005. Downloaded from

Figure 1 Patient 1 has oedema in both hands and feet, particularly in the latter (A), but this symptom quickly improved after starting oral prednisolone (B).

REFERENCES 6 Espinosa G, Font J, Munoz-Rodriguez FJ, Cervera R, Ingelmo M. Myelodysplastic and myeloproliferative syndromes associated with giant cell 1 Cantini F, Salvarani C, Olivieri I, Barozzi L, Macchioni L, Niccoli L, et al. arteritis and polymyalgia rheumatica: a coincidental coexistence or a causal Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) relationship? Clin Rheumatol 2002;21:309–13. http://ard.bmj.com/ syndrome: a prospective follow up and magnetic resonance imaging study. 7 McCarty DJ, O’Duffy JD, Pearson L, Hunter JB. Remitting seronegative Ann Rheum Dis 1999;58:230–6. symmetrical synovitis with pitting edema. RS3PE syndrome. JAMA 2 Cimmino MA, Silvestri E, Garlaschi G. Remitting seronegative symmetrical 1985;254:2763–7. synovitis with pitting oedema (RS3PE) as recurrence of aborted PMR. Ann 8 Cimmino MA, Salvarani C. Classification and assessment of rheumatic Rheum Dis 2001;60:303. diseases: polymyalgia rheumatica and giant cell arteritis. Baillieres Clin 3 Queiro R. RS3PE syndrome: a clinical and immunogenetical study. Rheumatol Rheumatol 1995;9:515–27. Int 2004;24:103–5. 9 Hoffman RW, O’Sullivan FX, Schafermeyer KR, Moore TL, Roussell D, 4 Oide T, Ohara S, Oguchi K, Maruyama M, Yazawa M, Inoue K, et al. Watson-McKown R, et al. Mycoplasma infection and rheumatoid arthritis: Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) analysis of their relationship using immunoblotting and an ultrasensitive on September 26, 2021 by guest. Protected copyright. syndrome in Nagano, Japan: clinical, radiological, and cytokine studies of 13 polymerase chain reaction detection method. Arthritis Rheum patients. Clin Exp Rheumatol 2004;22:91–8. 1997;40:1219–28. 5 Torres A, Cuende E, De Pablos M, Lezaun MJ, Michaus L, Vesga JC. Remitting 10 Elling P, Plsson AT, Elling H. Synchronous variations of the incidence of seronegative symmetrical synovitis with pitting edema associated with temporal arteritis and polymyalgia rheumatica in different regions of

subcutaneous Streptobacillus moniliformis abscess. J Rheumatol Denmark: association with epidemics of Mycoplasma pneumoniae infection.

2001;28:1696–8. J Rheumatol 1996;23:112–19.

€eripher—l neurop—thy in p—tients with systemi™ rheum—ti™

dise—ses tre—ted with leflunomide

g wetzlerD e g erltD ‡ v qrossD t fr—ndt

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enn ‚heum his PHHSYTRXIUWV±IVHHF doiX IHFIIQTG—rdFPHHSFHQVPTS

eflunomide @vipA w—s introdu™ed —s — new dise—se @€x€A h—s ˜een des™ri˜ed in eight p—tients with

I±Q

sn the modifying —ntirheum—ti™ drug in IWWVF p to rheum—toid —rthritis @‚eA —nd psori—ti™ —rthritisF

v now hep—totoxi™ityD hypertensionD —nd di—rrhoe— h—ve postm—rketing surveill—n™e €x€ does not —ppe—r —s — side

R

˜een reported —s —dverse eventsF €eripher—l neurop—thy effe™tF

www.annrheumdis.com Letters 1799

Ann Rheum Dis: first published as 10.1136/ard.2005.036715 on 11 November 2005. Downloaded from

„his first retrospe™tive study —imed —t ev—lu—ting whether

vip might ˜e —sso™i—ted with €x€ in — l—rge ™ohort of

p—tients with infl—mm—tory rheum—ti™ dise—sesF

ell inp—tients of — prim—ry rheum—tology ™lini™ with

systemi™ rheum—ti™ dise—ses —nd tre—tment with vip

˜etween eugust IWWV —nd w—y PHHR were retrospe™tively

‚emission ‚emission ƒt—˜le ƒt—˜le ƒt—˜le ƒt—˜le ƒt—˜le ƒt—˜le

s™reened for — new onset of €x€F €—tients with definite

re—sons for €x€Ðfor ex—mpleD —™tive v—s™ulitis or ™oll—geE

nosisD di—˜etes mellitusD l—™k of vit—minsD —l™ohol —˜useD —nd

Q neopl—smsD were ex™ludedF €x€ w—s s™reened ™lini™—lly —nd P T

pollow up @monthsA yut™ome

™onfirmed ˜y ele™trophysiologi™—l ex—min—tionF

ƒeven hundred —nd eighty five p—tients with vip tre—tment

were identifiedF €x€ w—s di—gnosed in IHT @IQFS7A p—tientsF

xinety five p—tients were ex™luded with di—˜etes @PP

‡—shEout Q p—tientsAD m—lignom— with ™ytotoxi™ tre—tment @P p—tientsAD ƒtopped ‡—shEout RV gontinued IR ƒtopped QW ƒtopped ƒtopped

v—s™ulitis @TU p—tientsAD —nd ™onne™tive tissue dise—ses @R

p—tientsAF xone of the p—tients with €x€ —nd systemi™

rheum—ti™ dise—ses potenti—lly —sso™i—ted with €x€ h—d —ny

history of neurop—thy or —ny ™lini™—l or serologi™—l signs of

dise—se —™tivity —t the time of the first m—nifest—tion of €x€ —nd wereD for ex—mpleD in remissionF

exon—l ‡—shEout PV ƒt—˜le exon—l gontinued RS ƒt—˜le exon—l hemyelising exon—l exon—lGdemyelising gontinued IP exon—l exon—l ileven of UVS @IFR7A p—tients were identified —s h—ving €x€

th—t w—s possi˜ly rel—ted to vip @t—˜le IAF „hese II p—tients

re™eived vip in — dose of PH±SH mgGd—y ˜y mouth d—ily for ‚e

in six p—tientsD ‡egener9s gr—nulom—tosis in twoD —nd for other

C infl—mm—tory rheum—ti™ dise—ses in three p—tientsD respe™E C C C C C C C ± ±

tivelyF €x€ h—d o™™urred within — medi—n of W months @r—nge

P±RVA —fter the st—rt of vipF ile™troneurogr—phy —nd ele™troE

myogr—phy showed th—t €x€ rel—ted to vip h—d —n —™rodist—l

hose of vip @mgGd—yAPH vo—ding dose „ype of €x€ gonsequen™e symmetri™ p—ttern in —ll p—tientsF „here w—s eviden™e of — PH ± exon—l ƒtopped S ‚emission QH PH SH PH PH PH PH PH PH

mostly —xon—l —ffe™tion in seven p—tients —nd demyelising

™h—nges in twoF €—tients with €x€ indu™ed ˜y vip were followed up for — medi—n of IP months @r—nge P±RSAF sn eight

P R U W R V

wonths vip ˜efore onset of €x€ II p—tients vip w—s stopped —ndD in —dditionD w—shed out in three IS IR RV IW

of themF €x€ improved in QGV @QUFS7A p—tients when vip w—s

stopped —nd rem—ined st—˜le in eightD independently of

stopping or ™ontinuing tre—tment with vipF

„his retrospe™tive —n—lysis supports —n —sso™i—tion ˜etween

tre—tment with vip —nd the o™™urren™e of €x€F gomp—r—˜le d—t—

—˜out the epidemiology of €x€ —re r—reY in IWWP ‡—lters et —l

http://ard.bmj.com/

des™ri˜ed — prev—len™e of PFW7 in — ™ohort of RVH he—lthy

S

™ontrolsF ‡hether there is — dose dependent neurotoxi™ effe™t of

vip is un™le—rF yne p—tient of our ™ohort est—˜lished — €x€ —fter

—n —™™ident—l int—ke of — higher dose vip @SH mgGd—yAF sn

™ontr—st with this experien™eD no in™re—se of €x€ w—s seen in two

w„ˆD €‚ihD €‚ihD omepr—zoleD —mitriptylineD lors—rt—nD metoprolol €‚ihD metoprololD omepr—zoleD —spirinD —terov—st—tin €‚ih €‚ihD ™—ptoprilD —spirinD furosemideD rofe™oxi˜ €‚ihD omepr—zoleD en—l—prilD —mitriptylineD risedron—te €‚ihD —torv—st—tinD metoprololD ™—ptoprilD p—ntopr—zole €‚ihD nitr—teD —spirinD simv—st—tinD ˜isoprolol w„ˆD €‚ihD phenpro™oumonD lors—rt—nD —mlodipin €‚ihD en—l—prilD omepr—zoleD w„ˆD €‚ihD ver—p—mil

different studies in whi™h PH p—tients with ‡egener9s gr—nuloE

T

—nd in m—tosis were tre—ted with QH±RH mgGd—y vip for P ye—rs

— prelimin—ry report of II p—tients with ‚e who re™eived vip in — on September 26, 2021 by guest. Protected copyright.

S S V S S S S

IW U IU IQ IT D D D D D dos—ge of RH mg for — me—n period of RFR monthsF „he underlying p—thogeneti™ me™h—nism is still unknownF

Ègren9s syndromeY ‡qD ‡egener9s gr—nulom—tosisY qgeD gi—nt ™ell —rteritisY w„ˆD methotrex—teD €‚ihD prednisoloneF ‡hen vip w—s first used for the tre—tment of ‚e the possi˜ility

th—t vip might indu™e v—s™ulitis w—s dis™ussed —fter — report of

V

— new onset of se™ond—ry v—s™ulitis in two p—tients with ‚eF sn

eutoE —nti˜odies g‚€ @mgGlA gon™omit—nt drugs ‚p neg exeD ƒƒe ™exgeG€‚Q ™exgeG€‚Q

C the me—ntime further s—fe —nd effe™tive tre—tment of prim—ry

T

systemi™ v—s™ulitides did not support this hypothesisF „hus one

might —rgue th—t vip w—s not effe™tive enough to suppress —

se™ond—ry v—s™ulitis in these two ™—sesF snterestinglyD in three

p—tients with ‚e —nd vip rel—ted €x€ nerve ˜iopsies were

performed showing — predomin—nt —xonop—thi™ pro™ess —nd

p ‚e ‚p neg v—s™ulitis of the —rteriolesF p‚e‚p p‚e‚p p‚e‚p p ‡q pw ‚e uƒpe rveEfPU pwqge ‡q p ƒƒ p‚e‚p

sn ™on™lusionD €x€ is — new —dverse event of vipF

„herefore we re™ommend ™lose neurologi™—l monitoring

S during tre—tment with vipF sn suspe™t ™—ses stopping —nd V H P R

ege —t onset of prim—ry dise—se ƒex hi—gnosis US RV SS w—shing out of vip ˜y ™holestyr—mine should ˜e ™onsideredF

gh—r—™teristi™s of II p—tients with peripher—l neurop—thy @€x€A rel—ted to tre—tment with leflunomide @vipA

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euthors9 —ffili—tions

hep—rtment of ‚heum—tologyD VRQ g wetzlerD ‡ v qrossD t fr—ndtD IU RS SQ PT UQ

IR RR €—tient xo IH SW II IP ‚eD rheum—toid —rthritisY uƒpeD undifferenti—ted spondylo—rthitisY ƒƒD ƒjo IQ

„—˜le I niversity of ƒ™hleswigErolsteinD g—mpus vue˜e™k —nd ‚heum—klinik f—d fr—mstedtD qerm—ny

www.annrheumdis.com 1800 Letters Ann Rheum Dis: first published as 10.1136/ard.2005.036715 on 11 November 2005. Downloaded from

A C Arlt, Department of Neurology, Rheumaklinik Bad Bramstedt, 2 Hill CL. Leflunomide-induced peripheral neuropathy: rapid resolution with Germany cholestyramine wash-out. Rheumatology (Oxford) 2004;43:809. 3 Bharadwaj A, Haroon N. Peripheral neuropathy in patients on leflunomide. Correspondence to: Dr C Metzler, University Hospital of Schleswig- Rheumatology (Oxford) 2004;43:934. Holstein, Campus Luebeck, Department of Rheumatology, Ratzeburger 4 van Riel PL, Smolen JS, Emery P, Kalden JR, Dougados M, Strand CV, et al. Leflunomide: a manageable safety profile. J Rheumatol Suppl 2004;71:21–4. Allee 160, D-23538 Luebeck, Germany; [email protected] 5 Walters DP, Gatling W, Mullee MA, Hill RD. The prevalence of diabetic distal sensory neuropathy in an English community. Diabet Med 1992;9:349–53. Accepted 14 May 2005 6 Metzler C, Fink C, Lamprecht P, Gross WL, Reinhold-Keller E. Mainenance of remission with leflunomide in Wegener’s granulomatosis. Rheumatology (Oxford), 2004;43:315–20. REFERENCES 7 Fiehn C, Rochel E, Ho AD, Max R. Dose escalation of leflunomide (LEF) to 40 mg once daily in patients with rheumatoid arthritis and insufficient response to standard dose LEF. Ann Rheum Dis 2004;63:746–77.

1 Carulli MT, Davies UM. Peripheral neuropathy: an unwanted effect of 8 Bruyn GAW, Griep EN, Korff KJ. Leflunomide for active rheumatoid arthritis.

leflunomide? Rheumatology (Oxford) 2002;41:952–3. Lancet 1999;353:1883–4.

†—s™ulitisD —ntiphospholipid —nti˜odiesD —nd ren—l —rtery

stenosis

ƒ x €—ulD ƒ ‚ ƒ—ngleD e x fennettD w ilEr—™hmiD ‚ r—ng—rtnerD q ‚ rughesD h € h9gruz

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enn ‚heum his PHHSYTRXIVHH±IVHPF doiX IHFIIQTG—rdFPHHSFHRHPUW

„—˜le I in™ludes four other p—tients with prim—ry ntiphospholipid —nti˜odies @—€vA —re ™onsidered to ˜e

v—s™ulitisD —€vD persistent hypertensionD —nd ‚eƒF nonEp—thogeni™ in p—tients with v—s™ulitisF ‡e present

‚en—l dise—se is not un™ommon in ‡qD ghurgEƒtr—ussD —nd e five p—tients with prim—ry v—s™ulitis who h—d —€v —nd

P

ntre—ted it m—y le—d to end st—ge mi™ros™opi™ poly—ngiitisF ren—l —rtery stenosis @‚eƒAY one of these p—tients h—d

ren—l f—ilureF rypertension seen in v—s™ulitis m—y ˜e ™oexistent ren—l p—thology due to prim—ry v—s™ulitisD —nd

se™ond—ry to ™orti™osteroid tre—tment or ren—l dise—seF mi™roE —nd m—™rop—thology due to ren—l m—nifest—tions of

etheros™lerosis is the m—jor ™—use of ‚eƒ @FWH7AD with — the —ntiphospholipid syndromeF

Q

minority of ™—ses due to fi˜romus™ul—r dyspl—si—F e RR ye—r old white smoker presented with sinusitisD

rypertension is — re™ognised fe—ture of —ntiphospholipid h—emoptysisD —nd —rthritisF ƒhe w—s normotensiveF e ™hest x

syndromeF ‚e™entlyD — high prev—len™e of ‚eƒ @PT7A w—s r—y demonstr—ted ™—vit—ting lesionsF ƒhe w—s ™exge positive

demonstr—ted in rel—tively young hypertensive p—tients with —nd fulfilled the emeri™—n gollege of ‚heum—tology ™riteri—

R

I

—ntiphospholipid syndromeF sn our ™ohortD —ll the stenoti™ —€v were dete™tedD for ‡egener9s gr—nulom—tosis @‡qAF

lesions were well defined —nd dist—l to the osti—D —nd the —lthough she l—™ked — history of throm˜oses or pregn—n™y

—ort—e showed no eviden™e of —theros™lerosisF mor˜idityF rer serum g re—™tive protein level w—s r—ised —t

http://ard.bmj.com/

‡e ˜elieve th—t ‚eƒ seen in our ™ohort m—y ˜e —sso™i—ted IHH mgGlF glini™—l —nd serologi™—l remission w—s —™hieved

with —€vF „he rel—tively young —ge of our p—tients —nd the with intr—venous ™y™lophosph—mide followed ˜y m—inteE

—˜sen™e of —therom—tous —ort—e on m—gneti™ reson—n™e n—n™e methotrex—te —nd ™orti™osteroid tre—tmentF

—ngiogr—phy —rgues —g—inst the —theros™leroti™ type of ‚eƒ efter dis™ontinuing ™orti™osteroidsD she ˜e™—me hypertenE

seen in elderly p—tientsF e possi˜le me™h—nism for the sive —nd her previously norm—l ren—l fun™tion deterior—tedF

development ‚eƒ in our ™ohort is throm˜osisD —™™eler—ted

rer serum ™re—tinine rose to ISR mmolGl —nd she developed

R

—theros™lerosisD —ndGor smooth mus™le hypertrophyF mild proteinuri— @HFRI gGPR hoursAF rer ™exge titre rose to

i—rlier reports h—ve suggested th—t the presen™e of —€v in on September 26, 2021 by guest. Protected copyright.

RH with — rise in erythro™yte sediment—tion r—te to PV mmGIst

ST

prim—ry v—s™ulitis is not p—thogeni™F „here —re no reports to hF ƒhe rem—ined —€v positiveF ‚epe—t e™ho™—rdiogr—phy

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www.annrheumdis.com Letters 1801 Ann Rheum Dis: first published as 10.1136/ard.2005.036715 on 11 November 2005. Downloaded from

Figure 1 (A) Haematoxylin and eosin renal biopsy stain demonstrating a large cellular crescent (Cr) and intraluminal thrombus. (B) Periodic acid- Schiff/methanamine silver stain of renal biopsy specimen. The glomerular capillary walls and mesangial matrix are black. The folding/crenation (single arrow) suggests ischaemic contraction. (C) Renal angiogram demonstrating right renal artery ostial stenosis with post-stenotic dilatation (black arrows). Note the smooth non-atheromatous appearance of the aorta. (D) Percutaneous transluminal angioplasty of right renal artery stenosis (white arrows). A colour version of the figure can be seen at http://www.annrheumdis.com/supplemental. http://ard.bmj.com/

Table 1 Patients with primary vasculitis, aPL, persistent hypertension, and RAS

Type of vasculitis, organ involvement, Renal artery stenosis on September 26, 2021 by guest. Protected copyright. Patient No, sex and treatment ANCA history aPL and thrombosis history

1, female* WG diagnosed age 44 cANCA R RAS diagnosed 4 years Positive lupus anticoagulant on more Respiratory, joint, renal after vasculitis than two occasions Cyclophosphamide, corticosteroids Cardiac valve lesions, renal thrombotic microangiopathy 2, male Churg-Strauss diagnosed age 46 pANCA L RAS diagnosed 18 years Positive lupus anticoagulant on two Cerebral vasculitis, cardiomyopathy, asthma, after vasculitis occasions sinusitis, necrotising glomerulonephritis 1 Cerebrovascular accident Corticosteroids, azathioprine, methotrexate, 1 Deep vein thrombosis cyclophosphamide 3, female WG diagnosed age 47 cANCA Bilateral RAS and coeliac Positive lupus anticoagulant and Pulmonary haemorrhage, crescentic artery stenosis diagnosed anticardiolipin antibodies on two glomerulonephritis, peripheral neuropathy 7 years after onset of occasions Azathioprine, cyclophosphamide, co-trimoxazole vasculitis Miscarriages, superficial thrombophlebitis 4, male WG diagnosed age 56 cANCA L RAS, superior mesenteric Lupus anticoagulant positive on two Pulmonary haemorrhage, epistaxis, and scleritis artery stenosis diagnosed occasions Methotrexate, cyclophosphamide, prednisolone, 4 years after onset of No thromboses co-trimoxazole vasculitis 5, female Primary idiopathic systemic vasculitis diagnosed Not present Bilateral RAS diagnosed Positive lupus anticoagulant on two age 42 15 years after onset of occasions Inflammatory arthropathy, coronary arteritis vasculitis Azathioprine, methotrexate, prednisolone

*Described above.

www.annrheumdis.com 1802 Letters

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Therapeutic interleukin (IL) 1 blockade normalises increased IL1b and decreased tumour necrosis factor a and IL10 production in blood mononuclear cells of a patient with CINCA syndrome M Seitz, R K Kamgang, H U Simon, P M Villiger ......

Ann Rheum Dis 2005;64:1802–1803. doi: 10.1136/ard.2005.036749

utations in the cold-induced autoinflammatory syn- leucocyte and platelet counts decreased, whereas monocyte drome 1 (CIAS1) gene cause inherited chronic numbers did not change and lymphocyte counts increased Mautoinflammatory disorders such as Muckle-Wells/ (table 1). familial cold urticaria and chronic infantile neurological At the functional level we did observe an enormous IL1b cutaneous and articular (CINCA) syndrome.12Up regulation release from monocytes after LPS stimulation before treat- of interleukin (IL) 1b was recently reported in unstimulated ment. This dramatically and progressively declined upon monocytes obtained from a patient with CINCA syndrome,3 treatment with anakinra. Surprisingly, the secretion of IL6 and active inflammatory disease resolved rapidly and from activated PBMC was completely blocked, and similar to completely during treatment with anakinra in patients with our previous finding in the same patient,7 we observed a CINCA4 and with Muckle-Wells syndrome.56 completely deficient IL10 and in this case a deficient TNFa We report on a 47 year old male patient with the CIAS1 response of monocytes to LPS stimulation before treatment. http://ard.bmj.com/ mutation T348M presenting classical clinical features of CINCA Therapeutic IL1 blockade, however, restored both, sponta- syndrome. The disease was refractory to conventional anti- neous as well as LPS-induced TNFa and IL10 secretion. inflammatory drugs and infliximab, but was successfully treated Based on the pretreatment findings on stimulation of with daily subcutaneous injections of 100 mg of recombinant PBMC in this patient, and in addition to our previous human IL1 receptor antagonist (anakinra, Kineret; Amgen, Cambridge, UK). Before and after therapeutic IL1 blockade, we assessed clinical and humoral inflammatory disease activity and Table 1 Laboratory measures in a patient with CINCA cytokine release (IL1b, tumour necrosis factor a (TNFa), IL6, and syndrome before and during treatment with recombinant on September 26, 2021 by guest. Protected copyright. IL10 in cell culture supernatants; R&D enzyme linked immuno- human IL1 receptor antagonist sorbent assay (ELISA) kits with lower detection limits of 3.9, 15.6, 3.13, and 7.8 pg/ml) from Ficoll-isolated and either Measure Baseline 3 Weeks 9 Weeks unstimulated or lipopolysaccharide (LPS; 100 ng/ml) stimulated 6 C reactive protein (mg/l) 47 9 4 peripheral blood mononuclear cells (PBMC; 1610 /ml RPMI Erythrocyte sedimentation rate 40 3 8 1640 +5% fetal calf serum) after 48 hours of cell culture. (mm/1st h) Cell-specific staining for monocytes was performed with Haemoglobin (g/l) 10.9 12.5 11.6 Leucocyte count (109/l) 15.6 8.1 9.4 mouse FITC-antihuman CD14 (eBioscience; San Diego, CA). Monocyte count (109/l) 0.47 0.50 0.47 Flow cytometry data were acquired only with propidium iodide Lymphocyte count (109/l) 1.4 2.87 2.87 negative cells on a FACSCalibur equipped with four lasers, and Platelet count (109/l) 528 403 419 data were analysed using CellQuest software (BD Biosciences). CD14+ cells among PBMC (%) 1.28 1.35 1.15

Concomitant symptomatic drug treatment was kept Cytokine secretion by PBMC (pg/ml) unchanged. Before anakinra treatment the patient showed Spontaneous IL1b ,3.9 ,3.9 ,3.9 typical clinical and serological signs of active inflammatory LPS-induced IL1b 8534 2943 271 disease, including rash, polyarthritis of wrists and metacarpal Spontaneous IL6 ,3.13 ,3.13 ,3.13 joints, leucocytosis with neutrophilia, and a moderate acute LPS-induced IL6 1921 ,3.13 ,3.13 Spontaneous TNFa ,15.6 225 188 phase response. After 2 days the rash completely vanished and LPS-induced TNFa ,15.6 732 220 synovitis and morning stiffness had markedly improved. After Spontaneous IL10 ,7.8 162 170 3 weeks complete clinical remission with absence of cutaneous LPS-induced IL10 ,7.8 163 175 and articular symptoms was achieved. Raised C reactive protein levels and erythrocyte sedimentation rate normalised and

www.annrheumdis.com Letters 1803 Ann Rheum Dis: first published as 10.1136/ard.2005.036715 on 11 November 2005. Downloaded from finding,7 we suggest that there is a defect of LPS responsive- Correspondence to: Professor M Seitz, [email protected] ness of monocytes to the induction of TNFa and IL10. This case confirms the excellent response of CINCA Accepted 3 May 2005 syndrome to treatment with human IL1 receptor antagonist. Our results suggest that patients with this hereditary autoin- flammatory disorder may exhibit a profound dysregulation of REFERENCES IL1 and TNFa synthesis. However, we cannot exclude the 1 Hoffmann HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutations of a new gene encoding a putative pyrin-like protein causes familial cold possibility that the inability to detect TNFa before application autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet of IL1 receptor antagonist owed more to a rapid decay of TNFa 2001;29:301–5. rather than reduced production. As this dysregulation is 2 Neven B, Callebaut I, Pieur AM, Feldmann G, Bodemer C, Lepore L, et al. reversed by treatment with IL1 receptor antagonist, one may Molecular basis of the spectral expression of CIAS1 mutations associated with phygocytic cell-mediated autoinflammatory disorders CINCA/NOMID, MWS, argue that therapeutic inhibition of otherwise aberrant IL1b and FCU. Blood 2004;103:2809–15. secretion results in a compensatory up regulation or less decay 3 Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR, of TNFa to maintain the host’s capacity to react to microbial et al. De novo CIAS1 mutations, cytokine activation, and evidence of genetic agents and other types of danger signals. Furthermore, the heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated overall up regulation of the TNFa pathway by interaction at the autoinflammatory diseases. Arthritis Rheum 2002;46:3340–8. IL1 pathway illustrates that the cytokine imbalance is not due 4 Granel B, Serratrice J, Disdier P, Weiller PJ. Dramatic improvement with to a defect, but rather to a dysregulation. Finally, our results anakinra in a case of chronic infantile neurological cutaneous and articular (CINCA) syndrome. Rheumatology 2005;44:689–90. provide an explanation for the reason why TNF blocking agents 5 Hawkins PN, Lachmann HJ, McDermott MF. Interleukin-1-receptor are ineffective in certain autoinflammatory diseases. antagonist in the Muckle-Wells syndrome. N Engl J Med 2003;348:2583–4...... 6 Hawkins PN, Lachmann HJ, Aganna E, McDermott MF. Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum Authors’ affiliations 2004;50:607–12. M Seitz, R K Kamgang, P M Villiger, Department of Rheumatology and 7 Bihl T, Vassina E, Boettger MK, Goldbach-Mansky R, Seitz M, Villiger PM, Clinical Immunology/Allergology, University Hospital, Bern, Switzerland et al. The T348M mutated form of cryopyrin is associated with defective LPS- H U Simon, Department of Pharmacology, University of Bern, Bern, induced IL-10 production in CINCA syndrome. Ann Rheum Dis Switzerland 2005;64:1380–1.

Reversible posterior leucoencephalopathy in scleroderma W L Poon, C C Mok ......

Ann Rheum Dis 2005;64:1803–1804. doi: 10.1136/ard.2005.038273

34 year old Chinese woman with limited scleroderma microangiopathic haemolytic anaemia, and rapidly deteriorat- presented with rapid onset of mental confusion and ing renal function with acute oligouric renal failure (increase in http://ard.bmj.com/ Ageneralised tonic-clonic seizures. Her blood pressure serum creatinine from baseline of 86 to 495 mmol/l in 3 days). control had been unsatisfactory in the preceding 4 weeks There was, however, no evidence of left ventricular failure. despite the use of three anti-hypertensive agents, which Treatment was given in the intensive care unit with included an angiotensin converting enzyme inhibitor. infusions of labetalol (up to 150 mg/h) and iloprost (up to Malignant hypertension (blood pressure 240/140 mm Hg on 10 mg/h), large doses of captopril (150 mg/day), and haemo- admission) was evident, with typical fundoscopic abnormalities, dialysis. An urgent magnetic resonance imaging (MRI) scan on September 26, 2021 by guest. Protected copyright.

Figure 1 (A) Axial T2 weighted and (B) coronal fluid attenuated inversion recovery (FLAIR) images showing bilateral abnormal hyperintensities in the white matter of the cerebellum, cortex, and subcortical white matter of the occipital lobes (long arrows), and in the brain stem (short arrows).

www.annrheumdis.com 1804 Letters Ann Rheum Dis: first published as 10.1136/ard.2005.036715 on 11 November 2005. Downloaded from of the brain showed marked vasogenic oedema distributed RPLS has been described in many rheumatic diseases, symmetrically at the cortex, and subcortical white matter of including systemic lupus erythematosus, systemic vasculi- the occipital lobes, the cerebellum, and the brain stem (fig 1). tides, and the overlap syndromes.23However, we believe that With control of hypertension and dialysis support, she this is the first report of RPLS in adult patients with limited gradually regained full consciousness without neurological scleroderma. Prompt recognition and treatment of this deficits. A repeat MRI scan 2 weeks later demonstrated condition is essential as it is potentially reversible. complete resolution of the lesions. The clinical picture was compatible with a reversible posterior leucoencephalopathy ...... syndrome (RPLS). Authors’ affiliations W L Poon, Department of Diagnostic Radiology, Tuen Mun Hospital, RPLS is a clinical syndrome characterised by headache, Hong Kong seizures, visual disturbances, and confusion. The MRI finding C C Mok, Department of Medicine, Tuen Mun Hospital, Hong Kong is often characteristic, with abnormal T2 weighted hyper- intensity affecting primarily the white matter of the Correspondence to: Dr C C Mok, Department of Medicine, Tuen Mun territories of the posterior circulation.1 The cerebral cortex Hospital, Tsing Chung Koon Road, New Territories, Hong Kong; and the anterior circulation territories may also be affected, [email protected] but usually to a lesser extent. RPLS has been described in an Accepted 23 April 2005 increasing number of medical conditions, including hyper- tensive encephalopathy, eclampsia, neurotoxicity related to calcineurin inhibitors, and uraemic encephalopathy. REFERENCES Reversible vasogenic oedema is the underlying pathology of 1 Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, et al. A reversible the abnormal MRI signal intensities. The exact pathogenesis posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494–500. 2 Primavera A, Audenino D, Mavilio N, Cocito L. Reversible posterior of RPLS remains elusive but a break down of the autoregula- leucoencephalopathy syndrome in systemic lupus and vasculitis. Ann Rheum tion of cerebral blood flow and endothelial dysfunction Dis 2001;60:534–7. resulting in leakage of fluid into the interstitium has been 3 Yong PF, Hamour SM, Burns A. Reversible posterior leukoencephalopathy in a patient with systemic sclerosis/systemic lupus erythematosus overlap postulated. syndrome. Nephrol Dial Transplant 2003;18:2660–2.

Experimental infection with Plasmodium falciparum does not result in the induction of anticardiolipin antibodies in healthy volunteers J Damoiseaux, A van der Ven, R Hermsen, D Telgt, M Roestenberg, J W Cohen Tervaert, R Sauerwein

...... http://ard.bmj.com/

Ann Rheum Dis 2005;64:1804–1805. doi: 10.1136/ard.2005.039214

ntiphospholipid antibodies (aPL), particularly lupus Anopheles stephensi mosquitoes were infected with the anticoagulant or anticardiolipin antibodies (aCL), are chloroquine sensitive NF54 isolate of P falciparum at the diagnostic markers for the antiphospholipid syndrome, insectary, as previously described.5 Sets of female mosquitoes A on September 26, 2021 by guest. Protected copyright. which is characterised by venous or arterial thrombosis or were allowed to feed on the forearms for 10 minutes. obstetric complications, or both.1 aPL may also occur in Subsequent dissection was performed to confirm the association with a multitude of infectious agents. Asherson presence of sporozoites in the mosquito salivary glands. If and Cervera, while reviewing infection related aPL, men- not present, the feed was repeated until successful. tioned malaria as one of the parasitic infections that has been Volunteers were carefully monitored by assessing blood films associated with the presence of aPL.2 Indeed, two indepen- twice daily. Upon microscopic detection of parasites, volun- dent papers have described the high prevalence of aPL in teers were immediately treated with a standard curative patients with malaria. Jakobsen et al described the induction regimen of chloroquine. of IgM, but not IgG aPL during acute Plasmodium falciparum Blood was sampled one day before infection and 1, 7, 10, infection of Sudanese adults.3 The aPL were reactive with 12, and 20 days after infection. IgM and IgG aCL were cardiolipin, phosphatidylinositol, and phosphatidylcholine. analysed by commercial enzyme linked immunosorbent Facer and Agiostratidou examined adult patients of diverse assay (ELISA; Pharmacia Diagnostics, Freiburg, Germany) ethnicity with uncomplicated non-severe malaria.4 They in a serum dilution of 1:100. Results showed that all showed that P falciparum and P vivax infections are associated volunteers were negative for both IgM and IgG aCL before with the appearance of raised plasma levels of IgM and IgG infection and remained negative for these antibodies during aPL, and aCL were raised in over 75% of the patients with follow up. Thus, acute P falciparum infection does not result in malaria. Patients with P falciparum had high aPL IgG levels, the induction of aCL. exceeding the levels seen in positive controls.4 Because the Nevertheless, although there seems to be no causal relation observed association may lack a causal relation, we recently between malaria and aCL, the coexistence of aPL may further evaluated the induction of aPL in 10 healthy white volunteers complicate malarial infection. For instance, thrombocytope- upon infection with P falciparum. nia is often (,60%) seen in patients with malaria, and

www.annrheumdis.com Letters 1805 Ann Rheum Dis: first published as 10.1136/ard.2005.036715 on 11 November 2005. Downloaded from immune-mediated mechanisms have been suggested.67 Competing interest statement: None of the authors have any competing Furthermore, in Gambian children with malaria the titres interest. 3 of aPL are significantly higher in severe than in mild malaria. Ethics approval: This study was approved by the medical ethics However, a protective role of aPL has also been suggested. committee of the University Medical Centre Nijmegen. East African children with cerebral malaria had significantly lower titres of IgM anti-phosphatidylinositol antibodies than Correspondence to: Dr J Damoiseaux, [email protected] those with non-severe malaria.4 This is possibly explained by the neutralisation of the pathogenic properties of parasite Accepted 8 May 2005 derived phospholipid.8 Whatever the pathogenic role of aPL, our present results REFERENCES indicate that acute P falciparum infection does not induce 1 Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, et al. these antibodies in a white population. Whether aPL develop International consensus statement on preliminary classification criteria for during chronic infections remains to be determined. Because definite antiphospholipid syndrome: report of an international workshop. genetic factors have been demonstrated to be associated with Arthritis Rheum 1999;42:1309–11. 2 Asherson RA, Cervera R. Antiphospholipid antibodies and infections. Ann 9 the prevalence of aPL, it can be expected that people Rheum Dis 2003;62:388–93. originating from malaria endemic areas are more prone to 3 Jakobsen PH, Morris-Jones SD, Hviid L, Theander TG, Hoier-Madsen M, the induction of aPL. Therefore, analysis of aPL upon Bayoumi RA, et al. Anti-phospholipid antibodies in patients with Plasmodium falciparum malaria. Immunology 1993;79:653–7. experimental infection with P falciparum in healthy volun- 4 Facer CA, Agiostratidou G. High levels of anti-phospholipid antibodies in teers from malaria endemic areas may further unravel the uncomplicated and severe Plasmodium falciparum and in P. vivax malaria. causal relation between malaria and aPL. Clin Exp Immunol 1994;95:304–9. 5 Hermsen CC, Vlas SJ de, Gemert GJA van, Telgt DSC, Verhage DF, ...... Sauerwein RW. Testing vaccines in human experimental malaria: statistical analysis of parasitemia measured by a quantitative real-time polymerase Authors’ affiliations chain reaction. Am J Trop Med Hyg 2004;71:196–201. J Damoiseaux, J W Cohen Tervaert, Department of Clinical and 6 Kelton JG, Keystone J, Moore J, Denomme G, Tozman E, Glynn M, et al. Experimental Immunology, University Hospital Maastricht, PO Box Immune-mediated thrombocytopenia of malaria. J Clin Invest 5800, 6202 AZ Maastricht, the Netherlands 1983;71:832–6. A van der Ven, D Telgt, Department of Internal Medicine, University 7 Sorensen PG, Mickley H, Schmidt KG. Malaria-induced immune Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, the thrombocytopenia. Vox Sang 1984;47:68–72. 8 Daniel-Ribeiro CT, Zanini G. Autoimmunity and malaria: what are they doing Netherlands together? Acta Trop 2000;76:205–21. R Hermsen, M Roestenberg, R Sauerwein, Department of Medical 9 Domenico Sebastiani G, Minisola G, Galeazzi M. HLA class II alleles and Microbiology, University Medical Centre Nijmegen, PO Box 9101, 6500 genetic predisposition to the antiphospholipid syndrome. Autoimmun Rev HB Nijmegen, the Netherlands 2003;2:387–94.

Population based studies of biological antirheumatic drug use in southern Sweden: comparison with pharmaceutical sales http://ard.bmj.com/ P Geborek, E Nitelius, S Noltorp, H Petri, L Jacobsson, L Larsson, T Saxne, I Leden ......

Ann Rheum Dis 2005;64:1805–1807. doi: 10.1136/ard.2005.036715 on September 26, 2021 by guest. Protected copyright.

his study aimed at assessing the drug costs for biological figures were adjusted according to the census population treatments in a geographically defined area in southern registry during 2000–03. Owing to legal constraints, which do TSweden (Scania province, population 1 145 090, not allow direct data linkage between SSATG and prescrip- November 2002), and at identifying any geographical tion databases, SSATG derived annual theoretical costs and differences and changes with time in the overall use of these sales of pharmaceutical agents to outpatients during the compounds. Also, we wanted to investigate the completeness period 2000–03 (public domain) were broken down according of the registry held by the South Swedish Arthritis Treatment to the patient’s district of residency as the unifying concept. Group (SSATG).1 During the study period no economic To obtain an estimate of the costs per week of using the prescribing restrictions existed for these drugs in the region. different drugs we assumed the annual drug dosage to be The Swedish social security system covers all prescribed drug 2550 mg etanercept, 2100 mg infliximab, 1040 mg adalimu- costs exceeding SEK 1800 (J170) a year to all patients in mab, and 36 500 mg anakinra, respectively. Year-specific need, where need is based on their physician’s judgment. pharmacy unit drug costs were used. In 2002 the resulting Thus, the use of biological antirheumatic treatment was costs were SEK 144 935 (1 SEK = 0.1J) for etanercept, SEK limited only by restricted drug availability and capacity of the 108 539 for infliximab, SEK 143 377 for anakinra, and SEK administration facilities. Medical practice was, however, 112 895 for adalimumab. The estimated yearly consumption under strong influence by guidelines from the Swedish of etanercept and infliximab was based on a previous detailed Rheumatological Association. health economic study,2 whereas for anakinra and adalimu- SSATG data were used to explore annual and regional mab we used the dosage recommended by the manufac- relations, assessing the current and previous use of biological turers. Registry data was checked against an assumed disease agents, prescription costs, and patient’s diagnoses. The prevalence of 0.5% of the adult population.3

www.annrheumdis.com 1806 Letters Ann Rheum Dis: first published as 10.1136/ard.2005.036715 on 11 November 2005. Downloaded from

Number of patients treated with biological Total SSATG derived costs in agents in Region Skåne A Region Skåne B (source SSATG register) 100 1000 Etanercept RA Infliximab Psoriatic arthritis Anakinra 800 Spondarthritis 75 Adalimumab JCA Miscellaneous 600 50

Number 400 Million SEK 25 200

0 0

2000 2001 2002 2003 2000 2001 2002 2003

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www.annrheumdis.com Letters 1807 Ann Rheum Dis: first published as 10.1136/ard.2005.036715 on 11 November 2005. Downloaded from

(table 1) that the SSATG includes .90% of patients with L Jacobsson, Department of Rheumatology, Malmo¨University Hospital, arthritis currently treated with biological agents. This allows S-205 02 Malmo¨, Sweden reliable continuous documentation of effects and potential I Leden, Department of Internal Medicine, Kristianstad Hospital, S-291 side effects. Furthermore, a regional pharmacovigilance 85 Kristianstad, Sweden registry is also useful for assessing local differences in the Correspondence to: Dr P Geborek, [email protected] use of the drugs and for evaluation of monitoring costs. Accepted 14 April 2005 This study was supported by grants from O¨sterlund and Kock Foundations, King Gustav V 80 year fund, and Reumatikerfo¨rbundet. REFERENCES ...... 1 Geborek P, Crnkic M, Petersson IF, Saxne T. Etanercept, infliximab and Authors’ affiliations leflunomide in established rheumatoid arthritis. Clinical experience using a P Geborek, L Larsson, T Saxne, Department of Rheumatology, Lund structured follow-up programme in southern Sweden. Ann Rheum Dis University Hospital, S-221 85 Lund, Sweden 2002;61:793–8. E Nitelius, Department of Internal Medicine, Trelleborg Hospital, S-231 2 Kobelt G, Eberhardt K, Geborek P. TNF-Inhibitors in the treatment of 55 Trelleborg, Sweden rheumatoid arthritis in clinical practice. costs and outcomes in a follow-up study of patients with rheumatoid arthritis treated with etanercept or infliximab S Noltorp, Department of Internal Medicine, Helsingborg Hospital, S- in Southern Sweden. Ann Rheum Dis 2004;63:4–10. 251 87 Helsinborg, Sweden 3 Simonsson M, Bergman S, Jacobsson LT, Petersson IF, Svensson B. The H Petri, Department of Internal Medicine, Simrishamn Hospital, S-272 prevalence of rheumatoid arthritis in Sweden. Scand J Rheumatol 81 Simrishamn, Sweden 1999;28:340–3.

Anti-cyclic citrullinated peptide antibodies in patients with rheumatoid arthritis treated with anti-tumour necrosis factor agents A S Russell, W P Maksymowych, M de Silva ......

Ann Rheum Dis 2005;64:1807. doi: 10.1136/ard.2005.040436

e Rycke et al pointed out the interesting discord arthritis—nodules, pulmonary disease, etc—do not seem to between rheumatoid factor titre and the titre of anti- respond to these therapeutic agents might be a suggestion cyclic citrullinated peptide (anti-CCP) antibodies in worth considering.

D http://ard.bmj.com/ their patients responding to infliximab plus methotrexate treatment.1 ...... We have looked at 158 patients receiving either infliximab Authors’ affiliations or etanercept plus methotrexate and treated for a slightly A S Russell, W P Maksymowych, M de Silva, University of Alberta, longer period over 1 year, all of whom, by definition, had Edmonton T6G2S2, Canada responded with at least an ACR20, and in whom pretreat- Correspondence to: Dr A S Russell, [email protected] ment serum samples were available.

We found essentially the same result for anti-CCP Accepted 2 May 2005 on September 26, 2021 by guest. Protected copyright. antibodies. Twenty four (15%) serum samples were negative at the outset, one of these became strongly positive in the serum specimen after 1 year. Of those who were strongly REFERENCE positive, one became negative; otherwise the titres remained 1 De Rycke L, Verhelst X, Kruithof E, Van den Bosche F, Hoffman IEA, Veys EM, et al. Rheumatoid factor, but not anti-cyclic citrullinated peptide antibodies, is relatively stable. Whether this in any way reflects the modulated by infliximab treatment in rheumatoid arthritis. Ann Rheum Dis observation that the extra-articular features of rheumatoid 2005;64:299–302.

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